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1
Scaletti, Emma Rose, Karl S. Vallin, Lars Bräutigam, Antonio Sarno, Ulrika Warpman Berglund, Thomas Helleday, Pål Stenmark, and Ann-Sofie Jemth. "MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool." Journal of Biological Chemistry 295, no. 15 (March 6, 2020): 4761–72. http://dx.doi.org/10.1074/jbc.ra120.012636.
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MutT homologue 1 (MTH1) removes oxidized nucleotides from the nucleotide pool and thereby prevents their incorporation into the genome and thereby reduces genotoxicity. We previously reported that MTH1 is an efficient catalyst of O6-methyl-dGTP hydrolysis suggesting that MTH1 may also sanitize the nucleotide pool from other methylated nucleotides. We here show that MTH1 efficiently catalyzes the hydrolysis of N6-methyl-dATP to N6-methyl-dAMP and further report that N6-methylation of dATP drastically increases the MTH1 activity. We also observed MTH1 activity with N6-methyl-ATP, albeit at a lower level. We show that N6-methyl-dATP is incorporated into DNA in vivo, as indicated by increased N6-methyl-dA DNA levels in embryos developed from MTH1 knock-out zebrafish eggs microinjected with N6-methyl-dATP compared with noninjected embryos. N6-methyl-dATP activity is present in MTH1 homologues from distantly related vertebrates, suggesting evolutionary conservation and indicating that this activity is important. Of note, N6-methyl-dATP activity is unique to MTH1 among related NUDIX hydrolases. Moreover, we present the structure of N6-methyl-dAMP–bound human MTH1, revealing that the N6-methyl group is accommodated within a hydrophobic active-site subpocket explaining why N6-methyl-dATP is a good MTH1 substrate. N6-methylation of DNA and RNA has been reported to have epigenetic roles and to affect mRNA metabolism. We propose that MTH1 acts in concert with adenosine deaminase-like protein isoform 1 (ADAL1) to prevent incorporation of N6-methyl-(d)ATP into DNA and RNA. This would hinder potential dysregulation of epigenetic control and RNA metabolism via conversion of N6-methyl-(d)ATP to N6-methyl-(d)AMP, followed by ADAL1-catalyzed deamination producing (d)IMP that can enter the nucleotide salvage pathway.
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Baños, G., F. Martínez, J. I. Grimaldo, and M. Franco. "Adenosine participates in regulation of smooth muscle relaxation in aortas from rats with experimental hypothyroidism." Canadian Journal of Physiology and Pharmacology 80, no. 6 (June 1, 2002): 507–14. http://dx.doi.org/10.1139/y02-064.
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The contribution of adenosine receptors was evaluated in vascular relaxation in experimental hypothyroidism. Hypothyroid aortic rings contracted less than normal controls with noradrenaline, phenylephrine, and KCl; the difference was maintained after incubation with 1,3-dipropyl-8-p-sulfophenylxanthine (an A1 and A2 adenosine receptor blocker). The vascular relaxation induced by acetylcholine or carbachol was similar in normal and hypothyroid aortic rings. However, adenosine, N6-cyclopentyladenosine (an A1 adenosine receptor analogue), and 5'-N-ethylcarbox amidoadenosine (an A2 and A3 adenosine analogue) induced vasodilation that was larger in hypothyroid than in normal aortas. Nω-nitro-L-arginine methyl ester shifted the dose-response curves of adenosine, N6-cyclopentyladenosine, or 5'-N-ethylcarboxamidoadenosine to the right in both normal and hypothyroid vessels. The blocker 1,3-dipropyl-8-p-sulfophenylxanthine significantly reduced adenosine-induced relaxation in the hypothyroid but not in the normal aortic vessels. These results suggest that in hypothyroid aortas, a larger adenosine-mediated vasodilation is observed probably due to an increase in receptor number or sensitivity.Key words: adenosine receptors, nitric oxide, hypothyroidism, smooth muscle, rat aorta.
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Broadley, Kenneth J., Erica Burnell, Robin H. Davies, Alan T. L. Lee, Stephen Snee, and Eric J. Thomas. "The synthesis of a series of adenosine A3 receptor agonists." Organic & Biomolecular Chemistry 14, no. 15 (2016): 3765–81. http://dx.doi.org/10.1039/c6ob00244g.
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A series of 1′-(6-aminopurin-9-yl)-1′-deoxy-N-methyl-β-d-ribofuranuronamides that were characterised by 2-dialkylamino-7-methyloxazolo[4,5-b]pyridin-5-ylmethyl substituents on N6 of interest for screening as selective adenosine A3 receptor agonists, have been synthesised.
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Haynes, J., B. Obiako, W. J. Thompson, and J. Downey. "Adenosine-induced vasodilation: receptor characterization in pulmonary circulation." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 5 (May 1, 1995): H1862—H1868. http://dx.doi.org/10.1152/ajpheart.1995.268.5.h1862.
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Adenosine mediates vascular smooth muscle relaxation in the pulmonary circulation. The A2 receptor has been suggested to mediate adenosine-induced vasodilation (AIV). In this study, the effect(s) of selective adenosine agonist and antagonist on the hypoxic pressor response (HPR) was assessed in the isolated blood-perfused rat lung. Adenosine (0.075-7.5 mM) infusion (0.125 ml/min) into the pulmonary artery dose dependently attenuated the HPR. AIV was mimicked by 10 microM 5'-(N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine agonist. Adenosine- and NECA-induced vasodilation were attenuated by 67 microM 8-(p-sulfophenyl)theophylline. In contrast, NECA-induced vasodilation was not attenuated by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (1 microM). At 10 microM, a minimal vasodilatory effect was seen with the nonselective adenosine agonists CV-1808 and N6-(2-phenylisopropyl)adenosine (R-PIA) compared with NECA. The highly selective A2a agonist 2-[p-(2-carboxyethyl)phenyl amino]-5'-N-ethyl carboxamido adenosine (CGS-21680C, 10 microM) and A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 10 microM) had no vasodilatory effect. Neither the K+ channel blockers tetraethylammonium chloride (10 mM) and glibenclamide (100 microM) nor the NO synthase inhibitor N omega-nitro-L-arginine methyl ester attenuated NECA-induced vasodilation. These findings suggest that AIV is mediated via the A2b receptor and that AIV occurs via an NO-independent mechanism.
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Pan, Tao. "N6-methyl-adenosine modification in messenger and long non-coding RNA." Trends in Biochemical Sciences 38, no. 4 (April 2013): 204–9. http://dx.doi.org/10.1016/j.tibs.2012.12.006.
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Savelieva, Ekaterina M., Anastasia A. Zenchenko, Mikhail S. Drenichev, Anna A. Kozlova, Nikolay N. Kurochkin, Dmitry V. Arkhipov, Alexander O. Chizhov, Vladimir E. Oslovsky, and Georgy A. Romanov. "In Planta, In Vitro and In Silico Studies of Chiral N6-Benzyladenine Derivatives: Discovery of Receptor-Specific S-Enantiomers with Cytokinin or Anticytokinin Activities." International Journal of Molecular Sciences 23, no. 19 (September 26, 2022): 11334. http://dx.doi.org/10.3390/ijms231911334.
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Cytokinins, classical phytohormones, affect all stages of plant ontogenesis, but their application in agriculture is limited because of the lack of appropriate ligands, including those specific for individual cytokinin receptors. In this work, a series of chiral N6-benzyladenine derivatives were studied as potential cytokinins or anticytokinins. All compounds contained a methyl group at the α-carbon atom of the benzyl moiety, making them R- or S-enantiomers. Four pairs of chiral nucleobases and corresponding ribonucleosides containing various substituents at the C2 position of adenine heterocycle were synthesized. A nucleophilic substitution reaction by secondary optically active amines was used. A strong influence of the chirality of studied compounds on their interaction with individual cytokinin receptors of Arabidopsis thaliana was uncovered in in vivo and in vitro assays. The AHK2 and CRE1/AHK4 receptors were shown to have low affinity for the studied S-nucleobases while the AHK3 receptor exhibited significant affinity for most of them. Thereby, three synthetic AHK3-specific cytokinins were discovered: N6-((S)-α-methylbenzyl)adenine (S-MBA), 2-fluoro,N6-((S)-α-methylbenzyl)adenine (S-FMBA) and 2-chloro,N6-((S)-α-methylbenzyl)adenine (S-CMBA). Interaction patterns between individual receptors and specific enantiomers were rationalized by structure analysis and molecular docking. Two other S-enantiomers (N6-((S)-α-methylbenzyl)adenosine, 2-amino,N6-((S)-α-methylbenzyl)adenosine) were found to exhibit receptor-specific and chirality-dependent anticytokinin properties.
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Liu, Hui, Huaizhi Wang, Zhen Wei, Songyao Zhang, Gang Hua, Shao-Wu Zhang, Lin Zhang, et al. "MeT-DB V2.0: elucidating context-specific functions of N6-methyl-adenosine methyltranscriptome." Nucleic Acids Research 46, no. D1 (November 8, 2017): D281—D287. http://dx.doi.org/10.1093/nar/gkx1080.
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Imaeda, Akihiro, Fumiaki Tomoike, Mayu Hayakawa, Kosuke Nakamoto, Yasuaki Kimura, Naoko Abe, and Hiroshi Abe. "N6-methyl adenosine in siRNA evades immune response without reducing RNAi activity." Nucleosides, Nucleotides & Nucleic Acids 38, no. 12 (July 12, 2019): 972–79. http://dx.doi.org/10.1080/15257770.2019.1641205.
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Li, Zhiqing, Ping Zhao, and Qingyou Xia. "Epigenetic Methylations on N6-Adenine and N6-Adenosine with the same Input but Different Output." International Journal of Molecular Sciences 20, no. 12 (June 15, 2019): 2931. http://dx.doi.org/10.3390/ijms20122931.
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Epigenetic modifications on individual bases in DNA and RNA can encode inheritable genetic information beyond the canonical bases. Among the nucleic acid modifications, DNA N6-methadenine (6mA) and RNA N6-methyladenosine (m6A) have recently been well-studied due to the technological development of detection strategies and the functional identification of modification enzymes. The current findings demonstrate a wide spectrum of 6mA and m6A distributions from prokaryotes to eukaryotes and critical roles in multiple cellular processes. It is interesting that the processes of modification in which the methyl group is added to adenine and adenosine are the same, but the outcomes of these modifications in terms of their physiological impacts in organisms are quite different. In this review, we summarize the latest progress in the study of enzymes involved in the 6mA and m6A methylation machinery, including methyltransferases and demethylases, and their functions in various biological pathways. In particular, we focus on the mechanisms by which 6mA and m6A regulate the expression of target genes, and we highlight the future challenges in epigenetic regulation.
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Barrington, W. W., K. A. Jacobson, A. J. Hutchison, M. Williams, and G. L. Stiles. "Identification of the A2 adenosine receptor binding subunit by photoaffinity crosslinking." Proceedings of the National Academy of Sciences 86, no. 17 (September 1989): 6572–76. http://dx.doi.org/10.1073/pnas.86.17.6572.
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A high-affinity iodinated agonist radioligand for the A2 adenosine receptor has been synthesized to facilitate studies of the A2 adenosine receptor binding subunit. The radioligand 125I-labeled PAPA-APEC (125I-labeled 2-[4-(2-[2-[(4- aminophenyl)methylcarbonylamino]ethylaminocarbonyl]- ethyl)phenyl]ethylamino-5'-N-ethylcarboxamidoadenosine) was synthesized and found to bind to the A2 adenosine receptor in bovine striatal membranes with high affinity (Kd = 1.5 nM) and A2 receptor selectivity. Competitive binding studies reveal the appropriate A2 receptor pharmacologic potency order with 5'-N-ethylcarboxamidoadenosine (NECA) greater than (-)-N6-[(R)-1-methyl- 2-phenylethyl]adenosine (R-PIA) greater than (+)-N6-[(S)-1-methyl-2- phenylethyl]adenosine (S-PIA). Adenylate cyclase assays, in human platelet membranes, demonstrate a dose-dependent stimulation of cAMP production. PAPA-APEC (1 microM) produces a 43% increase in cAMP production, which is essentially the same degree of increase produced by 5'-N- ethylcarboxamidoadenosine (the prototypic A2 receptor agonist). These findings combined with the observed guanine nucleotide-mediated decrease in binding suggest that PAPA-APEC is a full A2 agonist. The A2 receptor binding subunit was identified by photoaffinity-crosslinking studies using 125I-labeled PAPA-APEC and the heterobifunctional crosslinking agent N-succinimidyl 6-(4'-azido-2'-nitrophenylamino)hexanoate (SANPAH). After covalent incorporation, a single specifically radiolabeled protein with an apparent molecular mass of 45 kDa was observed on NaDodSO4/PAGE/autoradiography. Incorporation of 125I-labeled PAPA-APEC into this polypeptide is blocked by agonists and antagonists with the expected potency for A2 receptors (see above) and is decreased in the presence of 10(-4) M guanosine 5'-[beta, gamma-imido]triphosphate. Photoaffinity crosslinking of the A1 adenosine receptor binding subunit with 125I-labeled 8-[4-[2-(4- aminophenylacetylamino)ethyl]carbonylmethyloxyphenyl]-1,3-di propylxanthine (PAPAXAC) (an A1 selective photoaffinity probe) in the same tissue reveals a 38-kDa peptide that exhibits the appropriate A1 receptor pharmacology. 125I-labeled PAPA-APEC, therefore, has identified the A2 receptor binding subunit as a 45-kDa protein that is unique and distinct from the A1 binding subunit.
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Zheng, Jingang, Rubio Wang, Edward Zambraski, Dan Wu, Kenneth A. Jacobson, and Bruce T. Liang. "Protective roles of adenosine A1, A2A, and A3 receptors in skeletal muscle ischemia and reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 6 (December 2007): H3685—H3691. http://dx.doi.org/10.1152/ajpheart.00819.2007.
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Although adenosine exerts cardio-and vasculoprotective effects, the roles and signaling mechanisms of different adenosine receptors in mediating skeletal muscle protection are not well understood. We used a mouse hindlimb ischemia-reperfusion model to delineate the function of three adenosine receptor subtypes. Adenosine A3 receptor-selective agonist 2-chloro- N6-(3-iodobenzyl)adenosine-5′- N-methyluronamide (Cl-IBMECA; 0.07 mg/kg ip) reduced skeletal muscle injury with a significant decrease in both Evans blue dye staining (5.4 ± 2.6%, n = 8 mice vs. vehicle-treated 28 ± 6%, n = 7 mice, P < 0.05) and serum creatine kinase level (1,840 ± 910 U/l, n = 13 vs. vehicle-treated 12,600 ± 3,300 U/l, n = 14, P < 0.05), an effect that was selectively blocked by an A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191; 0.05 mg/kg). The adenosine A1 receptor agonist 2-chloro- N6-cyclopentyladenosine (CCPA; 0.05 mg/kg) also exerted a cytoprotective effect, which was selectively blocked by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.2 mg/kg). The adenosine A2A receptor agonist 2- p-(2-carboxyethyl)phenethylamino-5′- N-ethylcarboxamidoadenosine (CGS-21680; 0.07 mg/kg)-induced decrease in skeletal muscle injury was selectively blocked by the A2A antagonist 2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e] [1,2,4]triazolo[1,5-C]pyrimidin-5-amine (SCH-442416; 0.017 mg/kg). The protection induced by the A3 receptor was abrogated in phospholipase C-β2/β3 null mice, but the protection mediated by the A1 or A2A receptor remained unaffected in these animals. The adenosine A3 receptor is a novel cytoprotective receptor that signals selectively via phospholipase C-β and represents a new target for ameliorating skeletal muscle injury.
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Felsch, A., K. Stöcker, and U. Borchard. "Phorbol ester-stimulated adherence of neutrophils to endothelial cells is reduced by adenosine A2 receptor agonists." Journal of Immunology 155, no. 1 (July 1, 1995): 333–38. http://dx.doi.org/10.4049/jimmunol.155.1.333.
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Abstract In this study we investigated the effect of adenosine receptor agonists on the adherence of PMA-stimulated human neutrophils to cultured porcine aortic endothelial cells. Additionally, we studied the influence of adenosine analogues on the second messenger cAMP in neutrophils and cultured endothelial cells. In the presence of 10 ng/ml PMA, there was a rapid and stable increase on adherence of neutrophils to the endothelial layer. The adenosine A2 receptor agonists, 2-(p-(2-carboxylethyl)phenethylamino)-5' N-ethylcarboxamido-adenosine (CGS 21680) (0.01 to 1 microM) and 5' N-ethylcarboxamidoadenosine (NECA) (0.01 to 1 microM) decreased the adherence of PMA-stimulated neutrophils maximally by 43% and 34%, respectively. In contrast the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (0.01 to 1 microM) showed a 30% increase in PMA-stimulated adherence of neutrophils to endothelial cells. CGS 21680 (0.01 to 1 microM) and NECA (0.01 to 1 microM) were without detectable effect on the formation of cAMP in neutrophils and endothelial cells; however, in the presence of the phosphodiesterase inhibitor Ro 20-1724 (70 microM), CGS 21680 and NECA maximally increased cAMP level 20-fold and 10-fold, respectively, in neutrophils, and 1.8-fold and 2-fold, respectively, in cultured endothelial cells. However, addition of 70 microM Ro 20-1724 to the adherence assay did not potentiate the inhibitory effects of CGS 21680 and NECA on PMA-stimulated neutrophil adherence. On the other hand, 2-chloro-N6-cyclopentyladenosine (0.01 to 1 microM) did not significantly alter cAMP level in neutrophils and endothelial cells in the presence of 4(3-butoxy-4-methoxyphenyl)methyl)-2-imidazolidinone (Ro 20-1724). Our results indicate that adenosine A2 receptor agonists decrease phorbol ester-stimulated adherence of neutrophils to cultured endothelial cells. This effect is possibly independent of adenosine A2 receptor-mediated stimulation of adenylate cyclase in neutrophils and cultured endothelial cells.
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Choi, Hongseok, Kenneth Jacobson, Jinha Yu, and Lak Jeong. "Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists." Pharmaceuticals 14, no. 4 (April 14, 2021): 363. http://dx.doi.org/10.3390/ph14040363.
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A new series of 4′-selenoadenosine-5′-N,N-dimethyluronamide derivatives as highly potent and selective human A3 adenosine receptor (hA3AR) antagonists, is described. The highly selective A3AR agonists, 4′-selenoadenosine-5′-N-methyluronamides were successfully converted into selective antagonists by adding a second N-methyl group to the 5′-uronamide position. All the synthesized compounds showed medium to high binding affinity at the hA3AR. Among the synthesized compounds, 2-H-N6-3-iodobenzylamine derivative 9f exhibited the highest binding affinity at hA3AR. (Ki = 22.7 nM). The 2-H analogues generally showed better binding affinity than the 2-Cl analogues. The cAMP functional assay with 2-Cl-N6-3-iodobenzylamine derivative 9l demonstrated hA3AR antagonist activity. A molecular modelling study suggests an important role of the hydrogen of 5′-uronamide as an essential hydrogen bonding donor for hA3AR activation.
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Niu, Yamei, Xu Zhao, Yong-Sheng Wu, Ming-Ming Li, Xiu-Jie Wang, and Yun-Gui Yang. "N6-methyl-adenosine (m6A) in RNA: An Old Modification with A Novel Epigenetic Function." Genomics, Proteomics & Bioinformatics 11, no. 1 (February 2013): 8–17. http://dx.doi.org/10.1016/j.gpb.2012.12.002.
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Fink, Cynthia A., Alfred P. Spada, Dennis Colussi, Luz Rivera, and Linda Merkel. "Synthesis of a Potent A1Selective Adenosine Agonist: N6-[1-R-[(3-Chloro-2-thienyl)methyl]propyl]adenosine, RG 14718(-)." Nucleosides and Nucleotides 11, no. 5 (June 1992): 1077–88. http://dx.doi.org/10.1080/07328319208021169.
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Olivera, A., M. Tomas, and J. M. Lopez-Novoa. "Effect of adenosine A1 and A2 agonists and antagonists on cAMP and Ca2+ in cultured rat mesangial cells." American Journal of Physiology-Cell Physiology 262, no. 4 (April 1, 1992): C840—C844. http://dx.doi.org/10.1152/ajpcell.1992.262.4.c840.
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Rat glomeruli have been shown to exhibit A1 and A2 adenosine (ADO) receptors. Adenosine also contracts isolated glomeruli and cultured mesangial cells (MC). We studied the effect of the relatively selective ADO agonists R-N6-(1-methyl-1-phenylethyl)adenosine (R-PIA; A1) and 5'-(N-ethylcarboxamido)-adenosine (NECA; A2) on adenosine 3',5'-cyclic monophosphate (cAMP) levels and 45Ca influx in MC. R-PIA (10(-6) M) induced a 55% decrease in cAMP content in 5 microM forskolin-pretreated MC. NECA (10(-6) M) significantly increases by 68% the cAMP levels of forskolin-stimulated MC. NECA-included increase on cAMP was absolutely blocked by the potent A2 antagonist PD115,199 and potentiated by the A1 antagonist PD116,948. Treatment with R-PIA plus the potent A2 antagonist PD115,199 increased 45Ca uptake approximately 40%, and NECA plus A1 antagonist PD116,948 induced a 25% decrease on 45Ca uptake with respect to basal 45Ca uptake. In summary, our studies show the coexistence of functional A1- and A2-like ADO receptors in glomerular MC. The A1 receptor inhibits and the A2 stimulates cAMP accumulation. In addition, the A1 ADO receptor stimulates and the A2 inhibits calcium uptake.
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Sturm, Christopher D., William A. Frisella, and Kong-Woo Yoon. "Attenuation of potassium cyanide-mediated neuronal cell death by adenosine." Journal of Neurosurgery 79, no. 1 (July 1993): 111–15. http://dx.doi.org/10.3171/jns.1993.79.1.0111.
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✓ Glutamate has been shown to play an important role in delayed neuronal cell death occurring due to ischemia. Attenuation of synaptically released glutamate can be accomplished by modulators such as adenosine and baclofen. This study focused on the ability of adenosine to attenuate the excitotoxicity secondary to glutamate receptor activation in vitro after exposure to potassium cyanide (KCN) in hippocampal neuronal cell cultures. For this study, hippocampal cell cultures were obtained from 1-day-old rats and trypan blue staining was used for assessment of cell viability. It was found that the N-methyl-D-aspartate-specific antagonist MK801 (10 µM) attenuated neuronal cell death resulting from exposure to 1 mM KCN for 60 minutes. Adenosine (10 to 1000 µM) decreased neuronal cell death secondary to the same concentration of KCN in a dose-dependent manner. This same neuroprotective effect is mimicked by the adenosine A1-specific receptor agonist N6-cyclopentyladenosine (10 µM). The A1-specific receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (10 to 1000 nM) blocked the neuroprotective effect of adenosine in a dose-dependent manner. Therefore, neuronal cell death produced by KCN in the experimental model described was mediated at least in part by glutamate. This neuronal cell death was attenuated by adenosine via the A1-specific mechanism.
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Gorman, Mark W., Kayoko Ogimoto, Margaret V. Savage, Kenneth A. Jacobson, and Eric O. Feigl. "Nucleotide coronary vasodilation in guinea pig hearts." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 3 (September 2003): H1040—H1047. http://dx.doi.org/10.1152/ajpheart.00981.2002.
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The role of P1 receptors and P2Y1 receptors in coronary vasodilator responses to adenine nucleotides was examined in the isolated guinea pig heart. Bolus arterial injections of nucleotides were made in hearts perfused at constant pressure. Peak increase in flow was measured before and after addition of purinoceptor antagonists. Both the P1 receptor antagonist 8-( p-sulfophenyl)theophylline and adenosine deaminase inhibited adenosine vasodilation. AMP-induced vasodilation was inhibited by P1 receptor blockade but not by adenosine deaminase or by the selective P2Y1 antagonist N6-methyl-2′-deoxyadenosine 3′,5′-bisphosphate (MRS 2179). ADP-induced vasodilation was moderately inhibited by P1 receptor blockade and greatly inhibited by combined P1 and P2Y1 blockade. ATP-induced vasodilation was antagonized by P1 blockade but not by adenosine deaminase. Addition of P2Y1 blockade to P1 blockade shifted the ATP dose-response curve further rightward. It is concluded that in this preparation ATP-induced vasodilation results primarily from AMP stimulation of P1 receptors, with a smaller component from ATP or ADP acting on P2Y1 receptors. ADP-induced vasodilation is largely due to P2Y1 receptors, with a smaller contribution by AMP or adenosine acting via P1 receptors. AMP responses are mediated solely by P1 receptors. Adenosine contributes very little to vasodilation resulting from bolus intracoronary injections of ATP, ADP, or AMP.
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Sun, Bin, Kaushal Kumar Bhati, Peizhe Song, Ashleigh Edwards, Louise Petri, Valdeko Kruusvee, Anko Blaakmeer, et al. "FIONA1-mediated methylation of the 3’UTR of FLC affects FLC transcript levels and flowering in Arabidopsis." PLOS Genetics 18, no. 9 (September 27, 2022): e1010386. http://dx.doi.org/10.1371/journal.pgen.1010386.
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Adenosine bases of RNA can be transiently modified by the deposition of a methyl-group to form N6-methyladenosine (m6A). This adenosine-methylation is an ancient process and the enzymes involved are evolutionary highly conserved. A genetic screen designed to identify suppressors of late flowering transgenic Arabidopsis plants overexpressing the miP1a microProtein yielded a new allele of the FIONA1 (FIO1) m6A-methyltransferase. To characterize the early flowering phenotype of fio1 mutant plants we employed an integrative approach of mRNA-seq, Nanopore direct RNA-sequencing and meRIP-seq to identify differentially expressed transcripts as well as differentially methylated RNAs. We provide evidence that FIO1 is the elusive methyltransferase responsible for the 3’-end methylation of the FLOWERING LOCUS C (FLC) transcript. Furthermore, our genetic and biochemical data suggest that 3’-methylation stabilizes FLC mRNAs and non-methylated FLC is a target for rapid degradation.
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Bozarov, Andrey, Yu-Zhong Wang, Jun Ge Yu, Jacqueline Wunderlich, Hamdy H. Hassanain, Mazin Alhaj, Helen J. Cooke, Iveta Grants, Tianhua Ren, and Fievos L. Christofi. "Activation of adenosine low-affinity A3 receptors inhibits the enteric short interplexus neural circuit triggered by histamine." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 6 (December 2009): G1147—G1162. http://dx.doi.org/10.1152/ajpgi.00295.2009.
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We tested the novel hypothesis that endogenous adenosine (eADO) activates low-affinity A3 receptors in a model of neurogenic diarrhea in the guinea pig colon. Dimaprit activation of H2 receptors was used to trigger a cyclic coordinated response of contraction and Cl− secretion. Contraction-relaxation was monitored by sonomicrometry (via intracrystal distance) simultaneously with short-circuit current ( Isc, Cl− secretion). The short interplexus reflex coordinated response was attenuated or abolished by antagonists at H2 (cimetidine), 5-hydroxytryptamine 4 receptor (RS39604), neurokinin-1 receptor (GR82334), or nicotinic (mecamylamine) receptors. The A1 agonist 2-chloro- N6-cyclopentyladenosine (CCPA) abolished coordinated responses, and A1 antagonists could restore normal responses. A1-selective antagonists alone [8-cyclopentyltheophylline (CPT), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX), or 8-cyclopentyl- N3-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-xanthine (FSCPX)] caused a concentration-dependent augmentation of crypt cell secretion or contraction and acted at nanomolar concentrations. The A3 agonist N6-(3-iodobenzyl)-adenosine-5′- N-methyluronamide (IB-MECA) abolished coordinated responses and the A3 antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS1191) could restore and further augment responses. The IB-MECA effect was resistant to knockdown of adenosine A1 receptor with the irreversible antagonist FSCPX; the IC50 for IB-MECA was 0.8 μM. MRS1191 alone could augment or unmask coordinated responses to dimaprit, and IB-MECA suppressed them. MRS1191 augmented distension-evoked reflex Isc responses. Adenosine deaminase mimicked actions of adenosine receptor antagonists. A3 receptor immunoreactivity was differentially expressed in enteric neurons of different parts of colon. After tetrodotoxin, IB-MECA caused circular muscle relaxation. The data support the novel concept that eADO acts at low-affinity A3 receptors in addition to high-affinity A1 receptors to suppress coordinated responses triggered by immune-histamine H2 receptor activation. The short interplexus circuit activated by histamine involves adenosine, acetylcholine, substance P, and serotonin. We postulate that A3 receptor modulation may occur in gut inflammatory diseases or allergic responses involving mast cell and histamine release.
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Ozkurede, Ulas, Rishabh Kala, Cameron Johnson, Ziqian Shen, Richard A. Miller, and Gonzalo G. Garcia. "Cap-independent mRNA translation is upregulated in long-lived endocrine mutant mice." Journal of Molecular Endocrinology 63, no. 2 (August 2019): 123–38. http://dx.doi.org/10.1530/jme-19-0021.
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It has been hypothesized that transcriptional changes associated with lower mTORC1 activity in mice with reduced levels of growth hormone and insulin-like growth factor 1 are responsible for the longer healthy lifespan of these mutant mice. Cell lines and tissues from these mice show alterations in the levels of many proteins that cannot be explained by corresponding changes in mRNAs. Such post-transcriptional modulation may be the result of preferential mRNA translation by the cap-independent translation of mRNA bearing the N6-methyl-adenosine (m6A) modification. The long-lived endocrine mutants – Snell dwarf, growth hormone receptor deletion and pregnancy-associated plasma protein-A knockout – all show increases in the N6-adenosine-methyltransferases (METTL3/14) that catalyze 6-methylation of adenosine (m6A) in the 5′ UTR region of select mRNAs. In addition, these mice have elevated levels of YTH domain-containing protein 1 (YTHDF1), which recognizes m6A and promotes translation by a cap-independent mechanism. Consistently, multiple proteins that can be translated by the cap-independent mechanism are found to increase in these mice, including DNA repair and mitochondrial stress response proteins, without changes in corresponding mRNA levels. Lastly, a drug that augments cap-independent translation by inhibition of cap-dependent pathways (4EGI-1) was found to elevate levels of the same set of proteins and able to render cells resistant to several forms of in vitro stress. Augmented translation by cap-independent pathways facilitated by m6A modifications may contribute to the stress resistance and increased healthy longevity of mice with diminished GH and IGF-1 signals.
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Haskó, G., C. Szabó, Z. H. Németh, V. Kvetan, S. M. Pastores, and E. S. Vizi. "Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice." Journal of Immunology 157, no. 10 (November 15, 1996): 4634–40. http://dx.doi.org/10.4049/jimmunol.157.10.4634.
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Abstract Adenosine released into the extracellular space by immunologic and nonimmunologic stimuli has been shown to regulate various immune functions. In this study we report that i.p. pretreatment of mice with CGS-21680 HCl (CGS), a selective agonist of A2 adenosine receptors, at 0.2 to 2 mg/kg caused an augmentation of plasma IL-10 levels induced by i.p. injection of LPS, but decreased plasma levels of LPS-induced TNF-alpha. 2-Chloro-N6-cyclopentyladenosine (CCPA), an agonist of A1 adenosine receptors, at 0.5 mg/kg diminished LPS-induced plasma TNF-alpha concentrations, but enhanced LPS-induced IL-10 levels only at the highest dose used (2 mg/kg). The specific A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-beta- D-ribofuranuronamide, at 0.2 and 0.5 mg/kg potentiated LPS-stimulated IL-10 production and inhibited LPS-induced TNF-alpha production. LPS-induced plasma nitrite and nitrate levels (the breakdown products of nitric oxide (NO)) were suppressed by CGS and CCPA. In the RAW 264.7 macrophage cell line, pretreatment of the cells with both CGS and CCPA inhibited LPS-induced IL-10, TNF-alpha, and NO production, each in a concentration-dependent manner. The inhibitory effect of these drugs on cytokine and NO production was associated with improved mitochondrial respiration. Neither CGS nor CCPA affected the LPS-induced nuclear translocation of transcription factor nuclear factor-kappaB in these cells. These results demonstrate that adenosine receptor stimulation differentially modulates the LPS-induced production of IL-10, TNF-alpha, and NO in vitro and in vivo. The increase in LPS-induced IL-10 production and suppression of LPS-induced TNF-alpha and NO production caused by adenosine receptor activation may explain some of the immunomodulatory actions of adenosine released in excess during inflammatory and/or ischemic insult.
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Spinaci, Andrea, Michela Buccioni, Daniela Catarzi, Chang Cui, Vittoria Colotta, Diego Dal Ben, Eleonora Cescon, et al. "“Dual Anta-Inhibitors” of the A2A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies." Pharmaceuticals 16, no. 2 (January 23, 2023): 167. http://dx.doi.org/10.3390/ph16020167.
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Based on a screening of a chemical library of A2A adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1δ) and to bind adenosine receptors (ARs). Some derivatives, here called “dual anta-inhibitors”, demonstrated good CK1δ inhibitory activity combined with a high binding affinity, especially for the A2AAR. The N6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17, IC50 = 0.59 μM and KiA2A = 0.076 μM) showed the best balance of A2AAR affinity and CK1δ inhibitory activity. Computational studies were performed to simulate, at the molecular level, the protein–ligand interactions involving the compounds of our series. Hence, the dual anta-inhibitor 17 could be considered the lead compound of new therapeutic agents endowed with synergistic effects for the treatment of chronic neurodegenerative and cancer diseases.
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Gu, Qihai, Ting Ruan, Ju-Lun Hong, Nausherwan Burki, and Lu-Yuan Lee. "Selected Contribution: Hypersensitivity of pulmonary C fibers induced by adenosine in anesthetized rats." Journal of Applied Physiology 95, no. 3 (September 2003): 1315–24. http://dx.doi.org/10.1152/japplphysiol.00107.2003.
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Compelling clinical evidence implicates the potential role of adenosine in development of airway hyperresponsiveness and suggests involvement of pulmonary sensory receptors. This study was carried out to determine the effect of a low dose of adenosine infusion on sensitivity of pulmonary C-fiber afferents in anesthetized open-chest rats. Infusion of adenosine (40 μg · kg-1 · min-1 iv for 90 s) mildly elevated baseline activity of pulmonary C fibers. However, during adenosine infusion, pulmonary C-fiber responses to chemical stimulants and lung inflation (30 cmH2O tracheal pressure) were markedly potentiated; e.g., the response to right atrial injection of capsaicin (0.25 or 0.5 μg/kg) was increased by more than fivefold (change in fiber activity = 2.64 ± 0.67 and 16.27 ± 3.11 impulses/s at control and during adenosine infusion, n = 13, P < 0.05), and this enhanced response returned to control in ∼10 min. The potentiating effect of adenosine infusion was completely blocked by pretreatment with 8-cyclopentyl-1,3-dipropylxanthine (100 μg/kg), a selective antagonist of the adenosine A1 receptor, but was not affected by 3,7-dimethyl-1-propargylxanthine (1 mg/kg), an A2-receptor antagonist, or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (2 mg/kg), an A3-receptor antagonist. This potentiating effect was also mimicked by N6-cyclopentyladenosine (0.25 μg·kg-1·min-1 for 90 s), a selective agonist of the adenosine A1 receptor. In conclusion, our results showed that infusion of adenosine significantly elevated the sensitivity of pulmonary C-fiber afferents in rat lungs and that this potentiating effect is likely mediated through activation of the adenosine A1 receptor.
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Lee, Ji Hoon, Juyeong Hong, Zhao Zhang, Bárbara de la Peña Avalos, Cecilia J. Proietti, Agustina Roldán Deamicis, Pablo Guzmán G., et al. "Regulation of telomere homeostasis and genomic stability in cancer by N6-adenosine methylation (m6A)." Science Advances 7, no. 31 (July 2021): eabg7073. http://dx.doi.org/10.1126/sciadv.abg7073.
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The role of RNA methylation on N6-adenosine (m6A) in cancer has been acknowledged, but the underlying mechanisms remain obscure. Here, we identified homeobox containing 1 (HMBOX1) as an authentic target mRNA of m6A machinery, which is highly methylated in malignant cells compared to the normal counterparts and subject to expedited degradation upon the modification. m6A-mediated down-regulation of HMBOX1 causes telomere dysfunction and inactivation of p53 signaling, which leads to chromosome abnormalities and aggressive phenotypes. CRISPR-based, m6A-editing tools further prove that the methyl groups on HMBOX1 per se contribute to the generation of altered cancer genome. In multiple types of human cancers, expression of the RNA methyltransferase METTL3 is negatively correlated with the telomere length but favorably with fractions of altered cancer genome, whereas HMBOX1 mRNA levels show the opposite patterns. Our work suggests that the cancer-driving genomic alterations may potentially be fixed by rectifying particular epitranscriptomic program.
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Röder, Konstantin, Amy M. Barker, Adrian Whitehouse, and Samuela Pasquali. "Investigating the structural changes due to adenosine methylation of the Kaposi’s sarcoma-associated herpes virus ORF50 transcript." PLOS Computational Biology 18, no. 5 (May 26, 2022): e1010150. http://dx.doi.org/10.1371/journal.pcbi.1010150.
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Kaposi’s sarcoma-associated herpes virus (KSHV) is a human oncovirus. KSHV relies on manipulating the host cell N6-methyl adenosine (m6A) RNA modification pathway to enhance virus replication. Methylation within a RNA stem loop of the open reading frame 50 (ORF50) increases transcript stability via the recruitment of the m6A reader, SND1. In this contribution we explore the energy landscapes of the unmethylated and methylated RNA stem loops of ORF50 to investigate the effect of methylation on the structure of the stem loop. We observe a significant shift upon methylation between an open and closed configuration of the top of the stem loop. In the unmethylated stem loop the closed configuration is much lower in energy, and, as a result, exhibits higher occupancy.
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Besada, Pedro, Liaman K. Mamedova, Krishnan K. Palaniappan, Zhan-Guo Gao, Bhalchandra V. Joshi, Lak Shin Jeong, Mortimer M. Civan, and Kenneth A. Jacobson. "Nucleoside Prodrugs of A3 Adenosine Receptor Agonists and Antagonists." Collection of Czechoslovak Chemical Communications 71, no. 6 (2006): 912–28. http://dx.doi.org/10.1135/cccc20060912.
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9-(β-D-Ribosfuranosyluronamide)adenine derivatives that are selective agonists and antagonists of the A3 adenosine receptor (AR) have been derivatized as prodrugs for in vivo delivery. The free hydroxy groups at the 2' and 3' positions of the agonists 2-chloro-N6-(3-iodobenzyl)-9-(N-methyl-(β-D-ribosfuranosyluronamide)adenine 2b, the corresponding 4'-thio nucleoside 2c, and antagonists 4a and 4b (5'-N,N-dimethylamides related to 2b and 2c, respectively) were derivatized through simple acylation reactions. The prodrug derivatives were tested in radioligand binding assays at ARs and in a functional assay of adenylate cyclase at the A3AR and found to be considerably less active than the parent drugs. The hydrolysis of nucleoside 2',3'-diesters to regenerate the parent compound in the presence of human blood was demonstrated. 2',3'-Dipropionate esters of 2b and 4a were readily cleaved in a two-step reaction to regenerate the parent drug, on a time scale of two hours. The cleavage of a 2',3'-dihexanoate ester occurred at a slower rate. This indicates that the prodrugs are suitable as masked forms of the biologically active A3AR agonists and antagonists for future evaluation in vivo.
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Qian, Qiang, James F. Curran, and Glenn R. Björk. "The Methyl Group of theN6-Methyl-N6-Threonylcarbamoyladenosine in tRNA of Escherichia coli Modestly Improves the Efficiency of the tRNA." Journal of Bacteriology 180, no. 7 (April 1, 1998): 1808–13. http://dx.doi.org/10.1128/jb.180.7.1808-1813.1998.
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ABSTRACT tRNA species that read codons starting with adenosine (A) containN 6-threonylcarbamoyladenosine (t6A) derivatives adjacent to and 3′ of the anticodons from all organisms. InEscherichia coli there are 12 such tRNA species of which two (tRNAGGU Thr1 and tRNAGGU Thr3) have the t6A derivativeN 6-methyl-N 6-threonylcarbamoyladenosine (m6t6A37). We have isolated a mutant ofE. coli that lacks the m6t6A37 in these two tRNAGGU Thr species. These tRNA species in the mutant are likely to have t6A37 instead of m6t6A37. We show that the methyl group of m6t6A37 originates fromS-adenosyl-l-methionine and that the gene (tsaA) which most likely encodes tRNA(m6t6A37)methyltransferase is located at min 4.6 on the E. coli chromosomal map. The growth rate of the cell, the polypeptide chain elongation rate, and the selection of Thr-tRNAGGU Thr to the ribosomal A site programmed with either of the cognate codons ACC and ACU were the same for thetsaA1 mutant as for the congenic wild-type strain. The expression of the threonine operon is regulated by an attenuator which contains in its leader mRNA seven ACC codons that are read by these two m6t6A37-containing tRNAGGU Thrspecies. We show that the tsaA1 mutation resulted in a twofold derepression of this operon, suggesting that the lack of the methyl group of m6t6A37 in tRNAGGU Thr slightly reduces the efficiency of this tRNA to read cognate codon ACC.
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Buck, L. T., and P. E. Bickler. "Role of adenosine in NMDA receptor modulation in the cerebral cortex of an anoxia-tolerant turtle (Chrysemys picta belli)." Journal of Experimental Biology 198, no. 7 (July 1, 1995): 1621–28. http://dx.doi.org/10.1242/jeb.198.7.1621.
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Accumulation of the neuromodulator adenosine in the anoxia-tolerant turtle brain may play a key role in a protective decrease in excitatory neurotransmission during anoxia. Since excitatory neurotransmission is mediated largely by Ca2+ entry through N-methyl-D-aspartate (NMDA) receptors, we measured the effect of adenosine on NMDA-mediated Ca2+ transients in normoxic and anoxic turtle cerebrocortical sheets. Intracellular [Ca2+] was measured fluorometrically with the Ca2+-sensitive dye Fura-2. Baseline intracellular [Ca2+] and [ATP] were also measured to assess cortical sheet viability and potential toxic effects of NMDA. Baseline [Ca2+] did not change significantly under any condition, ranging from 109 +/- 22 to 187 +/- 26 nmoll-1. Throughout normoxic and 2h anoxic protocols, and after single and multiple NMDA exposures, [ATP] did not change significantly, ranging from 16.0 +/- 1.9 to 25.3 +/- 4.9 nmol ATP mg-1 protein. Adenosine caused a reduction in the normoxic NMDA-mediated increase in [Ca2+] from a control level of 287 +/- 35 to 103 +/- 22 nmoll-1 (64%). This effect is mediated by the A1 receptor since 8-phenyltheophylline (a specific A1 antagonist) effectively blocked the adenosine effect and N6-cyclopentyladenosine (a specific A1 agonist) elicited a similar decrease in the NMDA-mediated response. Cortical sheets exposed to anoxia alone exhibited a 52% decrease in the NMDA-mediated [Ca2+] rise, from 232 +/- 30 to 111 +/- 9 nmoll-1. The addition of adenosine had no further effect and 8-phenyltheophylline did not antagonize the observed decrease. Therefore, the observed down-regulation of NMDA receptor activity during anoxia must involve additional, as yet unknown, mechanisms.
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Tian, Cheng, Yanlan Huang, Qimeng Li, Zhihui Feng, and Qiong Xu. "Mettl3 Regulates Osteogenic Differentiation and Alternative Splicing of Vegfa in Bone Marrow Mesenchymal Stem Cells." International Journal of Molecular Sciences 20, no. 3 (January 28, 2019): 551. http://dx.doi.org/10.3390/ijms20030551.
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Bone mesenchymal stem cells (BMSCs) can be a useful cell resource for developing biological treatment strategies for bone repair and regeneration, and their therapeutic applications hinge on an understanding of their physiological characteristics. N6-methyl-adenosine (m6A) is the most prevalent internal chemical modification of mRNAs and has recently been reported to play important roles in cell lineage differentiation and development. However, little is known about the role of m6A modification in the cell differentiation of BMSCs. To address this issue, we investigated the expression of N6-adenosine methyltransferases (Mettl3 and Mettl14) and demethylases (Fto and Alkbh5) and found that Mettl3 was upregulated in BMSCs undergoing osteogenic induction. Furthermore, we knocked down Mettl3 and demonstrated that Mettl3 knockdown decreased the expression of bone formation-related genes, such as Runx2 and Osterix. The alkaline phosphatase (ALP) activity and the formation of mineralized nodules also decreased after Mettl3 knockdown. RNA sequencing analysis revealed that a vast number of genes affected by Mettl3 knockdown were associated with osteogenic differentiation and bone mineralization. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that the phosphatidylinositol 3-kinase/AKT (PI3K-Akt) signaling pathway appeared to be one of the most enriched pathways, and Western blotting results showed that Akt phosphorylation was significantly reduced after Mettl3 knockdown. Mettl3 has been reported to play an important role in regulating alternative splicing of mRNA in previous research. In this study, we found that Mettl3 knockdown not only reduced the expression of Vegfa but also decreased the level of its splice variants, vegfa-164 and vegfa-188, in Mettl3-deficient BMSCs. These findings might contribute to novel progress in understanding the role of epitranscriptomic regulation in the osteogenic differentiation of BMSCs and provide a promising perspective for new therapeutic strategies for bone regeneration.
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McDonnell, Bronagh, Ross Hamilton, Miranda Fong, Sean M. Ward, and Kathleen D. Keef. "Functional evidence for purinergic inhibitory neuromuscular transmission in the mouse internal anal sphincter." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 4 (April 2008): G1041—G1051. http://dx.doi.org/10.1152/ajpgi.00356.2007.
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The neurotransmitter(s) underlying nitric oxide synthase (NOS)-independent neural inhibition in the internal anal sphincter (IAS) is still uncertain. The present study investigated the role of purinergic transmission. Contractile and electrical responses to electrical field stimulation of nerves (0.1–5 Hz for 10–60 s) were recorded in strips of mouse IAS. A single stimulus generated a 28-mV fast inhibitory junction potential (IJP) and relaxation. The NOS inhibitor Nω-nitro-l-arginine (l-NNA) reduced the fast IJP duration by 20%. Repetitive stimulation at 2.5–5 Hz caused a more sustained IJP and sustained relaxation. l-NNA reduced relaxation at 1 Hz and the sustained IJP at 2.5–5 Hz. All other experiments were carried out in the presence of NOS blockade. IJPs and relaxation were significantly reduced by the P2 receptor antagonists 4-[[4-formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-2-pyridinyl]azo]-1,3-benzenedisulfonic acid (PPADS) (100 μM), by desensitization of P2Y receptors with adenosine 5′-[β-thio]diphosphate (ADP-βS) (10 μM), and by the selective P2Y1 receptor blocker 2′-deoxy- N6-methyl adenosine 3′,5′-diphosphate (MRS2179) (10 μM). Relaxation and IJPs were also significantly reduced by the K+ channel blocker apamin (1 μM). Removal of extracellular potassium (Ko) increased IJP amplitude to 205% of control, whereas return of Ko 30 min later hyperpolarized cells by 19 mV and reduced IJP amplitude to 50% of control. Exogenous ATP (3 mM) relaxed muscles in the presence of TTX (1 μM) and hyperpolarized cells by 15 mV. In conclusion, these data suggest that purinergic transmission significantly contributes to NOS-independent neural inhibition in the mouse IAS. P2Y1 receptors, as well as at least one other P2 receptor subtype, contribute to this pathway. Purinergic receptors activate apamin-sensitive K+ channels as well as other apamin-insensitive conductances leading to hyperpolarization and relaxation.
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Ali, S., W. J. Metzger, H. A. Olanrewaju, and S. J. Mustafa. "Adenosine receptor-mediated relaxation of rabbit airway smooth muscle: a role for nitric oxide." American Journal of Physiology-Lung Cellular and Molecular Physiology 273, no. 3 (September 1, 1997): L581—L587. http://dx.doi.org/10.1152/ajplung.1997.273.3.l581.
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In this study, we investigated the relaxant effect of adenosine receptor agonists on KCl-precontracted airway smooth muscle from rabbits and characterized the type of receptor involved in bronchorelaxation in the presence and absence of epithelium. We further defined the role of epithelium-derived relaxing factor, i.e., nitric oxide (NO), on these responses. In both epithelium-intact and -denuded tertiary airway rings from rabbits, the adenosine receptor agonists 2-[p-(2-carboxyethyl)]phenylethylamino-5-N'-ethylcarboxamidoadenos ine (CGS-21680), 5'-(N-ethyl-carboxamido)adenosine (NECA), 2-chloroadenosine (CAD), and (-)-N6-(2-phenylisopropyl)adenosine (R-PIA) relaxed airway smooth muscle with a potency order of CGS-21680 > NECA > CAD > R-PIA. A 98.5, 89.7, 73.2, and 64.7% relaxation was observed at 10(-5) M by CGS-21680, NECA, CAD, and R-PIA in the epithelium-intact bronchial rings, respectively. The 50% maximum effective concentration (EC50; x 10(-7) M) values for CGS-21680, NECA, CAD, and R-PIA were 2, 4, 9, and 80, respectively. Denuded rings, however, showed much less relaxant responses to various adenosine agonists compared with epithelium-intact rings. The adenosine receptor antagonist 8-(sulfophenyl)theophylline significantly attenuated the relaxant responses to all the agonists in the epithelium-intact and -denuded rings. The epithelium-dependent relaxant effect of the agonists in airway rings was inhibited by NG-monomethyl-L-arginine (L-NMMA; 30 microM). The EC50 (x 10(-6) M) values for CGS-21680, NECA, CAD, and R-PIA in the presence of inhibitor were 5.5, 8, 30, and 200, respectively. The L-NMMA produced an insignificant inhibitory effect in the epithelium-denuded rings. L-Arginine but not D-arginine (100 microM) reversed the inhibitory effect of L-NMMA on adenosine agonist-induced relaxation. In primary epithelial cells in culture, CGS-21680 (10(-5) M) induced a fourfold increase in NO production over the control. The CGS-21680-induced NO production in epithelial cells was significantly inhibited by NG-nitro-L-arginine methyl ester (L-NAME). Moreover, L-arginine reversed the inhibitory effect of L-NAME in the epithelial cells. The data suggest that adenosine relaxes rabbit airway smooth muscle through an A2 adenosine receptor and the epithelium serves as a source of NO.
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Barrett, R. J., and D. A. Droppleman. "Interactions of adenosine A1 receptor-mediated renal vasoconstriction with endogenous nitric oxide and ANG II." American Journal of Physiology-Renal Physiology 265, no. 5 (November 1, 1993): F651—F659. http://dx.doi.org/10.1152/ajprenal.1993.265.5.f651.
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Renal vasoconstrictor responses to the adenosine A1 agonist N6-cyclopentyladenosine (CPA) were compared in the in situ autoperfused rat kidney to responses evoked by angiotensin II (ANG II), endothelin-1 (ET-1), arginine vasopressin (AVP), carbocyclic thromboxane A2 (CTxA2), phenylephrine (PE), and 5-hydroxytryptamine (5-HT). On the basis of their ED50 values (dose of agonist, in mass units, that produced 50% of maximal response to that agonist), the order of vasoconstrictor potency was ANG II > or = AVP > ET-1 > CPA > 5-HT > or = PE > CTxA2. Dose-response curves to CPA were shallower and maximal responses were weaker than those produced by the other agonists. Maximal responses, the log ED50, and the slope of the dose-response curve to CPA were markedly potentiated in the presence of the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Selective antagonism of A1 receptors increased renal blood flow and markedly attenuated CPA-induced renal vasoconstriction in the absence or presence of L-NAME but had no effect on the maximal responses to ANG II. Conversely, AT1 receptor antagonism attenuated renal vasoconstriction produced by ANG II but had little effect on the produced by CPA. These results suggest that endogenous NO modulates renal vasoconstriction produced by A1 receptor stimulation and provide evidence against an interaction between renovascular adenosine A1 and angiotensin AT1 receptors.
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Park, J. Y., I. G. Jun, and M. Y. Kwon. "The effects of A1 adenosine receptor agonists, (R)-N6-(1-Methyl-2-phenylethyl) adenosine (R-PIA) on the antiallodynic morphine tolerance in a rat model of postoperative pain." European Journal of Anaesthesiology 22, Supplement 34 (May 2005): 189. http://dx.doi.org/10.1097/00003643-200505001-00684.
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Obrietan, K., A. B. Belousov, H. C. Heller, and A. N. van den Pol. "Adenosine pre- and postsynaptic modulation of glutamate-dependent calcium activity in hypothalamic neurons." Journal of Neurophysiology 74, no. 5 (November 1, 1995): 2150–62. http://dx.doi.org/10.1152/jn.1995.74.5.2150.
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1. Within the hypothalamus, adenosine has been reported to influence temperature regulation, sleep homeostasis, and endocrine secretions. The effects of adenosine on hypothalamic neurons have not been studied at the cellular level. Adenosine (5 nM-30 microM) showed no influence on intracellular Ca2+ or electrical activity in the presence of glutamate receptor antagonists D-2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione; consequently, we examined the role of adenosine in modulating the activity of glutamate in cultured hypothalamic neurons (n > 1,700) with fura-2 Ca2+ digital imaging and whole cell patch-clamp electrophysiology in the absence of glutamate receptor block. 2. When glutamate receptors were not blocked, adenosine (1-30 microM) and the selective adenosine A1 receptor agonist N6-cyclopentyl adenosine (CPA; 5 nM-1 microM) caused a large reduction in intracellular Ca2+ and electrical activity, suggesting that glutamate neurotransmission was critical for an effect of adenosine to be detected. Neuronal Ca2+ levels were reversibly depressed by CPA (50 nM), with a maximum depression of 90%, and these effects were blocked by coadministration of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). 3. Ca2+ levels in immature neurons before the time of synaptogenesis were not affected by adenosine. Adenosine A1 receptor activation suppressed glutamate-mediated Ca2+ activity in neurons in vitro 8 to 73 days. 4. Adenosine (1 or 10 microM) caused a hyperpolarization of membrane potential and a reduction of large postsynaptic potentials arising from endogenously released glutamate. The administration of low concentrations of CPA (5 nM) decreased the frequency of glutamate-mediated, neuronally synchronized Ca2+ transients and the frequency of postsynaptic potentials. 5. To compare the relative effects of adenosine on hypothalamic neurons with cells from other brain regions, we assayed the effects of CPA on glutamate-mediated Ca2+ in hippocampal and cortical cultures. CPA (50 nM) reversibly depressed glutamate-mediated Ca2+ rises in hypothalamic neurons by 35%, compared with 54% in hippocampal neurons and 46% in cortical neurons. 6. If it does play a functional role, adenosine should be released by hypothalamic cells. In some neurons the adenosine A1 receptor antagonists cyclopentyltheophylline or DPCPX caused an increase in intracellular Ca2+, suggesting that adenosine was secreted by hypothalamic cells, tonically depressing glutamate-enhanced neuronal Ca2+. 7. To determine whether adenosine could exert a postsynaptic effect, we coapplied it with glutamate agonists in the presence of tetrodotoxin. Within subpopulations of hypothalamic neurons, adenosine and CPA either inhibited (18% of total neurons) or potentiated (6% of total neurons) responses to glutamate, N-methyl-D-aspartate, and kainate by > or = 20%. 8. In contrast to the modest effects found in neurons, responses of hypothalamic astrocytes to the application of glutamate or the metabotropic glutamate receptor agonist (+/-)-trans-1-amino-1,3-cyclopentanedicarboxylic acid were strongly potentiated by adenosine (mean +225%) and CPA. 9. Together, these findings suggest that adenosine exerts a major presynaptic effect and a minor postsynaptic effect in the modulation of glutamate neurotransmission in the hypothalamus, where it can play a significant role in blocking a large part of the glutamate-induced Ca2+ rise. In the absence of glutamate transmission, adenosine has relatively little effect on either neuronal intracellular Ca2+ or electrical activity.
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Carroll, S. M., P. Narayan, and F. M. Rottman. "N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA." Molecular and Cellular Biology 10, no. 9 (September 1990): 4456–65. http://dx.doi.org/10.1128/mcb.10.9.4456-4465.1990.
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N6-methyladenosine (m6A) residues occur at internal positions in most cellular and viral RNAs; both heterogeneous nuclear RNA and mRNA are involved. This modification arises by enzymatic transfer of a methyl group from S-adenosylmethionine to the central adenosine residue in the canonical sequence G/AAC. Thus far, m6A has been mapped to specific locations in eucaryotic mRNA and viral genomic RNA. We have now examined an intron-specific sequence of a modified bovine prolactin precursor RNA for the presence of this methylated nucleotide by using both transfected-cell systems and a cell-free system capable of methylating mRNA transcripts in vitro. The results indicate the final intron-specific sequence (intron D) of a prolactin RNA molecule does indeed possess m6A residues. When mapped to specific T1 oligonucleotides, the predominant site of methylation was found to be within the consensus sequence AGm6ACU. The level of m6A at this site is nonstoichiometric; approximately 24% of the molecules are modified in vivo. Methylation was detected at markedly reduced levels at other consensus sites within the intron but not in T1 oligonucleotides which do not contain either AAC or GAC consensus sequences. In an attempt to correlate mRNA methylation with processing, stably transfected CHO cells expressing augmented levels of bovine prolactin were treated with neplanocin A, an inhibitor of methylation. Under these conditions, the relative steady-state levels of the intron-containing nuclear precursor increased four to six times that found in control cells.
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Carroll, S. M., P. Narayan, and F. M. Rottman. "N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA." Molecular and Cellular Biology 10, no. 9 (September 1990): 4456–65. http://dx.doi.org/10.1128/mcb.10.9.4456.
Full textAbstract:
N6-methyladenosine (m6A) residues occur at internal positions in most cellular and viral RNAs; both heterogeneous nuclear RNA and mRNA are involved. This modification arises by enzymatic transfer of a methyl group from S-adenosylmethionine to the central adenosine residue in the canonical sequence G/AAC. Thus far, m6A has been mapped to specific locations in eucaryotic mRNA and viral genomic RNA. We have now examined an intron-specific sequence of a modified bovine prolactin precursor RNA for the presence of this methylated nucleotide by using both transfected-cell systems and a cell-free system capable of methylating mRNA transcripts in vitro. The results indicate the final intron-specific sequence (intron D) of a prolactin RNA molecule does indeed possess m6A residues. When mapped to specific T1 oligonucleotides, the predominant site of methylation was found to be within the consensus sequence AGm6ACU. The level of m6A at this site is nonstoichiometric; approximately 24% of the molecules are modified in vivo. Methylation was detected at markedly reduced levels at other consensus sites within the intron but not in T1 oligonucleotides which do not contain either AAC or GAC consensus sequences. In an attempt to correlate mRNA methylation with processing, stably transfected CHO cells expressing augmented levels of bovine prolactin were treated with neplanocin A, an inhibitor of methylation. Under these conditions, the relative steady-state levels of the intron-containing nuclear precursor increased four to six times that found in control cells.
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Lee, H. Thomas, Mihwa Kim, Jin Deok Joo, George Gallos, Jiang-Fan Chen, and Charles W. Emala. "A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 4 (October 2006): R959—R969. http://dx.doi.org/10.1152/ajpregu.00034.2006.
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The role of A3 adenosine receptors (ARs) in sepsis and inflammation is controversial. In this study, we determined the effects of A3AR modulation on mortality and hepatic and renal dysfunction in a murine model of sepsis. To induce sepsis, congenic A3AR knockout mice (A3AR KO) and wild-type control (A3AR WT) mice were subjected to cecal ligation and double puncture (CLP). A3AR KO mice had significantly worse 7-day survival compared with A3AR WT mice. A3AR KO mice also demonstrated significantly higher elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and TNF-α 24 h after induction of sepsis compared with A3AR WT mice. Renal cortices from septic A3AR KO mice exhibited increased mRNA encoding proinflammatory cytokines and enhanced nuclear translocation of NF-kB compared with samples from A3AR WT mice. A3AR WT mice treated with N6-(3-iodobenzyl)ADO-5′ N-methyluronamide (IB-MECA; a selective A3AR agonist) or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191; a selective A3AR antagonist) had improved or worsened 7-day survival after induction of sepsis, respectively. Moreover, A3AR WT mice treated with IB-MECA or MRS-1191 showed acutely improved or worsened, respectively, renal and hepatic function following CLP. IB-MECA significantly reduced mortality in mice lacking the A1AR or A2aAR but not the A3AR, demonstrating specificity of IB-MECA in activating A3ARs and mediating protection against sepsis-induced mortality. We conclude that endogenous or exogenous A3AR activation confers significant protection from murine septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
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Gallego, Diana, Pilar Hernández, Pere Clavé, and Marcel Jiménez. "P2Y1 receptors mediate inhibitory purinergic neuromuscular transmission in the human colon." American Journal of Physiology-Gastrointestinal and Liver Physiology 291, no. 4 (October 2006): G584—G594. http://dx.doi.org/10.1152/ajpgi.00474.2005.
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Indirect evidence suggests that ATP is a neurotransmitter involved in inhibitory pathways in the neuromuscular junction in the gastrointestinal tract. The aim of this study was to characterize purinergic inhibitory neuromuscular transmission in the human colon. Tissue was obtained from colon resections for neoplasm. Muscle bath, microelectrode experiments, and immunohistochemical techniques were performed. 2′-deoxy- N6-methyl adenosine 3′,5′-diphosphate tetraammonium salt (MRS 2179) was used as a selective inhibitor of P2Y1 receptors. We found that 1) ATP (1 mM) and adenosine 5′-β-2-thiodiphosphate (ADPβS) (10 μM), a preferential P2Y agonist, inhibited spontaneous motility and caused smooth muscle hyperpolarization (about −12 mV); 2) MRS 2179 (10 μM) and apamin (1 μM) significantly reduced these effects; 3) both the fast component of the inhibitory junction potential (IJP) and the nonnitrergic relaxation induced by electrical field stimulation were dose dependently inhibited (IC50 ∼1 μM) by MRS 2179; 4) ADPβS reduced the IJP probably by a desensitization mechanism; 5) apamin (1 μM) reduced the fast component of the IJP (by 30–40%) and the inhibitory effect induced by electrical field stimulation; and 6) P2Y1 receptors were localized in smooth muscle cells as well as in enteric neurons. These results show that ATP or a related purine is released by enteric inhibitory motoneurons, causing a fast hyperpolarization and smooth muscle relaxation. The high sensitivity of MRS 2179 has revealed, for the first time in the human gastrointestinal tract, that a P2Y1 receptor present in smooth muscle probably mediates this mechanism through a pathway that partially involves apamin-sensitive calcium-activated potassium channels. P2Y1 receptors can be an important pharmacological target to modulate smooth muscle excitability.
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Gallego, Diana, Víctor Gil, Jordi Aleu, Mariona Aulí, Pere Clavé, and Marcel Jiménez. "Purinergic and nitrergic junction potential in the human colon." American Journal of Physiology-Gastrointestinal and Liver Physiology 295, no. 3 (September 2008): G522—G533. http://dx.doi.org/10.1152/ajpgi.00510.2007.
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The aim of the present work is to investigate a putative junction transmission [nitric oxide (NO) and ATP] in the human colon and to characterize the electrophysiological and mechanical responses that might explain different functions from both neurotransmitters. Muscle bath and microelectrode techniques were performed on human colonic circular muscle strips. The NO donor sodium nitroprusside (10 μM), but not the P2Y receptor agonist adenosine 5′-O-2-thiodiphosphate (10 μM), was able to cause a sustained relaxation. NG-nitro-l-arginine (l-NNA) (1 mM), a NO synthase inhibitor, but not 2′-deoxy- N6-methyl adenosine 3′,5′-diphosphate tetraammonium salt (MRS 2179) (10 μM), a P2Y antagonist, increased spontaneous motility. Electrical field stimulation (EFS) at 1 Hz caused fast inhibitory junction potentials (fIJPs) and a relaxation sensitive to MRS 2179 (10 μM). EFS at higher frequencies (5 Hz) showed biphasic IJP with fast hyperpolarization sensitive to MRS 2179 followed by sustained hyperpolarization sensitive to l-NNA; both drugs were needed to fully block the EFS relaxation at 2 and 5 Hz. Two consecutive single pulses induced MRS 2179-sensitive fIJPs that showed a rundown. The rundown mechanism was not dependent on the degree of hyperpolarization and was present after incubation with l-NNA (1 mM), hexamethonium (100 μM), MRS 2179 (1 μM), and NF023 (10 μM). We concluded that single pulses elicit ATP release from enteric motor neurons that cause a fIJP and a transient relaxation that is difficult to maintain over time; also, NO is released at higher frequencies causing a sustained hyperpolarization and relaxation. These differences might be responsible for complementary mechanisms of relaxation being phasic (ATP) and tonic (NO).
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Ruocco, Miriam, Luca Ambrosino, Marlene Jahnke, Maria Chiusano, Isabel Barrote, Gabriele Procaccini, João Silva, and Emanuela Dattolo. "m6A RNA Methylation in Marine Plants: First Insights and Relevance for Biological Rhythms." International Journal of Molecular Sciences 21, no. 20 (October 12, 2020): 7508. http://dx.doi.org/10.3390/ijms21207508.
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Circadian regulations are essential for enabling organisms to synchronize physiology with environmental light-dark cycles. Post-transcriptional RNA modifications still represent an understudied level of gene expression regulation in plants, although they could play crucial roles in environmental adaptation. N6-methyl-adenosine (m6A) is the most prevalent mRNA modification, established by “writer” and “eraser” proteins. It influences the clockwork in several taxa, but only few studies have been conducted in plants and none in marine plants. Here, we provided a first inventory of m6A-related genes in seagrasses and investigated daily changes in the global RNA methylation and transcript levels of writers and erasers in Cymodocea nodosa and Zostera marina. Both species showed methylation peaks during the dark period under the same photoperiod, despite exhibiting asynchronous changes in the m6A profile and related gene expression during a 24-h cycle. At contrasting latitudes, Z. marina populations displayed overlapping daily patterns of the m6A level and related gene expression. The observed rhythms are characteristic for each species and similar in populations of the same species with different photoperiods, suggesting the existence of an endogenous circadian control. Globally, our results indicate that m6A RNA methylation could widely contribute to circadian regulation in seagrasses, potentially affecting the photo-biological behaviour of these plants.
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Zhang, Yu-Chen, Shao-Wu Zhang, Lian Liu, Hui Liu, Lin Zhang, Xiaodong Cui, Yufei Huang, and Jia Meng. "Spatially Enhanced Differential RNA Methylation Analysis from Affinity-Based Sequencing Data with Hidden Markov Model." BioMed Research International 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/852070.
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With the development of new sequencing technology, the entire N6-methyl-adenosine (m6A) RNA methylome can now be unbiased profiled with methylated RNA immune-precipitation sequencing technique (MeRIP-Seq), making it possible to detect differential methylation states of RNA between two conditions, for example, between normal and cancerous tissue. However, as an affinity-based method, MeRIP-Seq has yet provided base-pair resolution; that is, a single methylation site determined from MeRIP-Seq data can in practice contain multiple RNA methylation residuals, some of which can be regulated by different enzymes and thus differentially methylated between two conditions. Since existing peak-based methods could not effectively differentiate multiple methylation residuals located within a single methylation site, we propose a hidden Markov model (HMM) based approach to address this issue. Specifically, the detected RNA methylation site is further divided into multiple adjacent small bins and then scanned with higher resolution using a hidden Markov model to model the dependency between spatially adjacent bins for improved accuracy. We tested the proposed algorithm on both simulated data and real data. Result suggests that the proposed algorithm clearly outperforms existing peak-based approach on simulated systems and detects differential methylation regions with higher statistical significance on real dataset.
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Mermoud, Jacqueline E. "The Role of the m6A RNA Methyltransferase METTL16 in Gene Expression and SAM Homeostasis." Genes 13, no. 12 (December 8, 2022): 2312. http://dx.doi.org/10.3390/genes13122312.
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The RNA methylation of adenosine at the N6-position (m6A) has attracted significant attention because of its abundance and dynamic nature. It accounts for more than 80% of all RNA modifications present in bacteria and eukaryotes and regulates crucial aspects of RNA biology and gene expression in numerous biological processes. The majority of m6A found in mammals is deposited by a multicomponent complex formed between methyltransferase-like (METTL) proteins METTL3 and METTL14. In the last few years, the list of m6A writers has grown, resulting in an expansion of our understanding of the importance of m6A and the methylation machinery. The characterization of the less familiar family member METTL16 has uncovered a new function of the m6A methylation apparatus, namely the fine-tuning of the cellular levels of the major methyl donor S-adenosylmethionine (SAM). METTL16 achieves this by adjusting the levels of the enzyme that synthesizes SAM in direct response to fluctuations in the SAM availability. This review summarizes recent progress made in understanding how METTL16 can sense and relay metabolic information and considers the wider implications. A brief survey highlights similarities and differences between METTL16 and the better-known METTL3/14 complex, followed by a discussion of the target specificity, modes of action and potential roles of METTL16.
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Doherty, James, and Raymond Dingledine. "Regulation of Excitatory Input to Inhibitory Interneurons of the Dentate Gyrus During Hypoxia." Journal of Neurophysiology 77, no. 1 (January 1, 1997): 393–404. http://dx.doi.org/10.1152/jn.1997.77.1.393.
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Doherty, J. and R. Dingledine. Regulation of excitatory input to inhibitory interneurons of the dentate gyrus during hypoxia. J. Neurophysiol. 77: 393–404, 1997. The role of metabotropic glutamate receptors (mGluRs) and adenosine receptors in hypoxia-induced suppression of excitatory synaptic input to interneurons residing at the granule cell–hilus border in the dentate gyrus was investigated with the use of whole cell electrophysiological recording techniques in thin (250 μm) slices of immature rat hippocampus. Minimal stimulation evoked glutamatergic excitatory postsynaptic currents (EPSCs) in dentate interneurons in 68 ± 4% (mean ± SE) of trials during stimulation in the dentate granule cell layer (GCL) and 48 ± 3% of trials during stimulation in CA3. Hypoxic episodes, produced by switching the perfusing solution from 95% O2-5% CO2 to a solution containing 95% N2-5% CO2 for 3–5 min, rapidly and reversibly decreased the synaptic reliability, or probability of evoking an EPSC, from either input without reducing EPSC amplitude, consistent with a presynaptic suppression of transmitter release. The mGluR antagonist (+)-α-methyl-4-carboxyphenylglycine [(+)MCPG; 500 μM] did not alter synaptic reliability or mean EPSC amplitude in either pathway. However, (+)MCPG significantly attenuated hypoxic suppression of input from both pathways, suggesting that mGluRs activated by release of glutamate partially mediate hypoxic suppression of EPSCs to dentate interneurons. The mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 100 μM) rapidly decreased the reliability of excitatory transmission from both the GCL (19 ± 5% of control) and CA3 (39 ± 15% of control). ACPD also increased the frequency of spontaneous EPSCs and evoked a slow inward current in dentate interneurons. Exogenous adenosine (10–300 μM) decreased synaptic reliability for both pathways and reduced the frequency of spontaneous EPSCs, but did not cause a decrease in the mean amplitude of evoked EPSCs, consistent with a presynaptic suppression of excitatory input to dentate interneurons. Conversely, the selective adenosine A1 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (200 nM to 1 μM) and N6-cyclopentyl-9-methyladenine (1 μM) enhanced excitatory input to dentate interneurons by increasing synaptic reliability for both the GCL and CA3 inputs. Adenosine A1 receptor antagonists did not, however, reduce hypoxic suppression of excitatory input to dentate interneurons. These results indicate that hypoxia induces a presynaptic inhibition of excitatory input to dentate interneurons mediated in part by activation of mGluRs, but not adenosine A1 receptors, whereas both mGluRs and adenosine A1 receptors can depress excitatory input to dentate interneurons during normoxic stimulation. Regulation of excitatory input to dentate interneurons provides a mechanism to shape excitatory input to the hippocampus under both normal and pathological conditions.
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Volpini, Rosaria, Michela Buccioni, Diego Dal Ben, Catia Lambertucci, Carmen Lammi, Gabriella Marucci, Anna T. Ramadori, Karl-Norbert Klotz, and Gloria Cristalli. "Synthesis and Biological Evaluation of 2-Alkynyl-N6-methyl-5′-N-methylcarboxamidoadenosine Derivatives as Potent and Highly Selective Agonists for the Human Adenosine A3Receptor‡." Journal of Medicinal Chemistry 52, no. 23 (December 10, 2009): 7897–900. http://dx.doi.org/10.1021/jm900754g.
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Maione, S., V. de Novellis, L. Cappellacci, E. Palazzo, D. Vita, L. Luongo, L. Stella, et al. "The antinociceptive effect of 2-chloro-2′-C-methyl-N6-cyclopentyladenosine (2′-Me-CCPA), a highly selective adenosine A1 receptor agonist, in the rat." Pain 131, no. 3 (October 2007): 281–92. http://dx.doi.org/10.1016/j.pain.2007.01.013.
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Reeve, Alison J., Anthony H. Dickenson, and Nicola C. Kerr. "Spinal Effects of Bicuculline: Modulation of an Allodynia-Like State by an A1-Receptor Agonist, Morphine, and an NMDA-Receptor Antagonist." Journal of Neurophysiology 79, no. 3 (March 1, 1998): 1494–507. http://dx.doi.org/10.1152/jn.1998.79.3.1494.
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Reeve, Alison J., Anthony H. Dickenson, and Nicola C. Kerr. Spinal effects of bicuculline: modulation of an allodynia-like state by an A1-receptor agonist, morphine, and an NMDA-receptor antagonist. J. Neurophysiol. 79: 1494–1507, 1998. Single-unit recordings were made in the intact anesthetized rat of the responses of dorsal horn neurons to C-, Aδ-, and Aβ-fiber stimulation. The postdischarge and windup responses of the same cells along with responses to innocuous stimuli, prod and brush, also were measured. The effects of (−)-bicuculline-methobromide (0.5, 5, 50, and 250 μg) were observed on these neuronal responses. The C- and Aδ-fiber–evoked responses were facilitated significantly in a dose-dependent manner. The input was facilitated, but as the final overall response was not increased by the same factor, windup appeared to be reduced. However, postdischarge, resulting from the increase in the excitability produced by windup, tended to be facilitated. After doses of ≥5 μg bicuculline, stimulation at suprathreshold Aβ-fiber–evoked activity caused enhanced firing, mainly at later latencies corresponding to Aδ-fiber–evoked activity in normal animals. Few cells responded consistently to brush and so no significant change was observed. Responses evoked by innocuous pressure (prod) always were observed in cells that concurrently responded to electrical stimulation with a C-fiber response. This tactile response was facilitated significantly by bicuculline. The effects of N6-cyclopentyladenosine (N6-CPA), an adenosine A1-receptor agonist, was observed after pretreatment with 50 μg bicuculline, as were the effects of morphine and 7-chlorokynurenate (7-CK). N6-CPA inhibited prod, C- and Aδ-fiber–evoked responses as well as the initial and overall final response to the train of C-fiber strength stimuli. Inhibitions were reversed with 8(p-sulphophenyl) theophylline. Morphine, the mu-receptor agonist, also inhibited the postbicuculline responses to prod, C-, and Aδ-fiber responses and initial and final responses to a train of stimuli. Inhibitory effects of morphine were reversed partly by naloxone. 7-CK, an antagonist at the glycine site on the N-methyl-d-aspartate-receptor complex, inhibited the responses to C- and Aδ-fiber–evoked activity as well as prod. The postdischarges were inhibited by this drug. Again both the initial and overall responses of the cell were inhibited. To conclude, bicuculline caused an increase in the responses of deep dorsal horn cells to prod, Aδ-fiber–evoked activity, increased C-fiber input onto these cells along with the appearance of responses at latencies normally associated with Aδ fibers, but evoked by suprathreshold Aβ-fiber stimulation. These alterations may be responsible for some aspects of the clinical phenomenon of allodynia and hyperalgesia. These altered and enhanced responses were modulated by the three separate classes of drugs, the order of effectiveness being 7-CK, N6-CPA, and then morphine.
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Ma, Marcella, Heather P. Harding, Stephen O'Rahilly, David Ron, and Giles S. H. Yeo. "Kinetic analysis of FTO (fat mass and obesity-associated) reveals that it is unlikely to function as a sensor for 2-oxoglutarate." Biochemical Journal 444, no. 2 (May 11, 2012): 183–87. http://dx.doi.org/10.1042/bj20120065.
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Genomewide-association studies have revealed that SNPs (single nucleotide polymorphisms) in FTO (fat mass and obesity-associated) are robustly associated with BMI (body mass index) and obesity. FTO is an Fe(II) 2-OG (2-oxoglutarate)-dependent dioxygenase that can demethylate 3-meT (3-methylthymine) in single-stranded DNA, as well as 3-meU (3-methyluracil) and N6-methyl adenosine in RNA. In the present paper we describe the development of an RNase-cleavage assay measuring the demethylation activity of FTO on 3-meU. RNase A cleaves at the 3′-end of pyrimidines, including uracil, and a methyl group at position three of uracil inhibits cleavage. An oligonucleotide probe was designed consisting of a DNA stem, an RNA loop containing a single 3-meU as the only RNase A-cleavage site, a fluorescent reporter on one end and a quencher at the other end. FTO demethylation of the unique 3-meU enables RNase A cleavage, releasing the quencher and enabling a fluorescent signal. In the presence of excess RNase A, FTO activity is limiting to the development of fluorescent signal, which can be read continuously and is able to discriminate between wild-type and the catalytically dead R316Q FTO. 2-OG is a co-substrate of FTO and, as a metabolite in the citric acid cycle, is a marker of intracellular nutritional status. The assay described in the present paper was used to measure, for the first time, the Km of FTO for 2-OG. The Km of 2.88 μM is up to 10-fold lower than the estimated intracellular concentrations of 2-OG, rendering it unlikely that FTO functions as a sensor for 2-OG levels.
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Hou, Qinghua, Yanfeng Zhong, Linzhuang Liu, Liusheng Wu, and Jixian Liu. "Construction of a lung adenocarcinoma prognostic model based on N6-methyl-adenosine-related long noncoding RNA and screening of potential drugs based on this model." Anti-Cancer Drugs 33, no. 4 (February 24, 2022): 371–83. http://dx.doi.org/10.1097/cad.0000000000001277.
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Laryushkin, Denis P., Sergei A. Maiorov, Valery P. Zinchenko, Valentina N. Mal’tseva, Sergei G. Gaidin, and Artem M. Kosenkov. "Of the Mechanisms of Paroxysmal Depolarization Shifts: Generation and Maintenance of Bicuculline-Induced Paroxysmal Activity in Rat Hippocampal Cell Cultures." International Journal of Molecular Sciences 24, no. 13 (July 1, 2023): 10991. http://dx.doi.org/10.3390/ijms241310991.
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Abnormal depolarization of neuronal membranes called paroxysmal depolarization shift (PDS) represents a cellular correlate of interictal spikes. The mechanisms underlying the generation of PDSs or PDS clusters remain obscure. This study aimed to investigate the role of ionotropic glutamate receptors (iGluRs) in the generation of PDS and dependence of the PDS pattern on neuronal membrane potential. We have shown that significant depolarization or hyperpolarization (by more than ±50 mV) of a single neuron does not change the number of individual PDSs in the cluster, indicating the involvement of an external stimulus in PDS induction. Based on this data, we have suggested reliable protocols for stimulating single PDS or PDS clusters. Furthermore, we have found that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are necessary for PDS generation since AMPAR antagonist NBQX completely suppresses bicuculline-induced paroxysmal activity. In turn, antagonists of NMDA (N-methyl-D-aspartate) and kainate receptors (D-AP5 and UBP310, respectively) caused a decrease in the amplitude of the first action potential in PDSs and in the amplitude of the oscillations of intracellular Ca2+ concentration occurring alongside the PDS cluster generation. The effects of the NMDAR (NMDA receptor) and KAR (kainate receptor) antagonists indicate that these receptors are involved only in the modulation of paroxysmal activity. We have also shown that agonists of some Gi-coupled receptors, such as A1 adenosine (A1Rs) or cannabinoid receptors (CBRs) (N6-cyclohexyladenosine and WIN 55,212-2, respectively), completely suppressed PDS generation, while the A1R agonist even prevented it. We hypothesized that the dynamics of extracellular glutamate concentration govern paroxysmal activity. Fine-tuning of neuronal activity via action on Gi-coupled receptors or iGluRs paves the way for the development of new approaches for epilepsy pharmacotherapy.