Journal articles on the topic 'M1 muscarinic acetylcholine receptor'
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Greig, Chasen J., Sarah J. Armenia, and Robert A. Cowles. "The M1 muscarinic acetylcholine receptor in the crypt stem cell compartment mediates intestinal mucosal growth." Experimental Biology and Medicine 245, no. 14 (July 1, 2020): 1194–99. http://dx.doi.org/10.1177/1535370220938375.
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Maintenance of the highly plastic intestinal epithelium relies upon stem cells localized to intestinal crypts. Recent evidence suggests muscarinic acetylcholine signaling impacts epithelial barrier function, proliferation, and apoptosis. We hypothesized that the intestinal crypt base would express specific muscarinic acetylcholine receptors that drive proliferation in this critical region. Intestinal segments spanning the small bowel were procured from wild-type C57Bl/6 mice to determine muscarinic acetylcholine receptor mRNA expression and create sections on laser capture microdissection slides for analysis of crypt base cells. RT-PCR was performed using primers targeting the five muscarinic acetylcholine receptor subtypes (M1–M5), LGR5, BIII-tubulin, and GAPDH. To determine the effects of muscarinic agonism in vivo, osmotic pumps delivering the M1 muscarinic acetylcholine receptor agonist McN-A-343 were implanted into wild type mice for one week. Segments were harvested, histologic sections created, and morphometric and proliferative parameters measured. In full-thickness intestinal samples, muscarinic acetylcholine receptor subtypes M1–M4 were found in all regions, while M5 was localized to the proximal jejunum. In crypt-base cells, the M1 muscarinic acetylcholine receptor subtype was the only subtype found and was present in all regions. LGR5 was present in all laser capture microdissection samples, indicating the capture of intestinal stem cells. In vivo experiments conducted with McN-A-343 revealed significantly increased villus height, crypt depth, and crypt-cell proliferation. The presence of M1 muscarinic acetylcholine receptor mRNA within the stem cell niche in the intestinal crypt base coupled with increased mucosal growth with M1 receptor stimulation in vivo suggests that the cholinergic system, via the M1 muscarinic acetylcholine receptor, is a critical mediator of intestinal mucosal homeostasis. Impact statement Localization of a specific subtype of the muscarinic acetylcholine receptor in the crypt stem cell compartment suggests a critical role in intestinal mucosal homeostasis. Here we demonstrate the localization of the M1 muscarinic acetylcholine receptor to the stem cell compartment and demonstrate increase morphometric and proliferative parameters when this is stimulated in vivo. These data provide novel information about this complex signaling microenvironment and offer potential future therapeutic targets for future study.
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Hollmann, Markus W., Lars G. Fischer, Anne M. Byford, and Marcel E. Durieux. "Local Anesthetic Inhibition of m1 Muscarinic Acetylcholine Signaling." Anesthesiology 93, no. 2 (August 1, 2000): 497–509. http://dx.doi.org/10.1097/00000542-200008000-00030.
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Background Local anesthetics inhibit lipid mediator signaling (lysophosphatidate, thromboxane) by acting on intracellular domains of the receptor or on the G protein. On receptors for polar agonists, the ligand-binding pocket could form an additional site of interaction, possibly resulting in superadditive inhibition. The authors therefore investigated the effects of local anesthetics on m1 muscarinic receptor functioning. Methods The authors expressed receptors in isolation using Xenopus oocytes. Using a two-electrode voltage clamp, the authors measured the effects of lidocaine, QX314 (permanently charged), and benzocaine (permanently uncharged) on Ca2+-activated Cl- currents elicited by methylcholine. The authors also characterized the interaction of lidocaine with [3H] quinuclydinyl benzylate ([3H]QNB) binding to m1 receptors. Results Lidocaine inhibited muscarinic signaling with a half-maximal inhibitory concentration (IC50 18 nm) 140-fold less than that of extracellularly administered QX314 (IC50 2.4 microm). Intracellularly injected QX314 (IC50 0.96 mm) and extracellularly applied benzocaine (IC50 1.2 mm) inhibited at high concentrations only. Inhibition of muscarinic signaling by extracellularly applied QX314 and lidocaine was the result of noncompetitive antagonism. Intracellularly injected QX314 and benzocaine inhibited muscarinic and lysophosphatidate signaling at similar concentrations, suggesting an action on the common G-protein pathway. Combined administration of intracellularly injected (IC50 19 microm) and extracellularly applied QX314 (IC50 49 nm) exerted superadditive inhibition. Lidocaine did not displace specific [3H]QNB binding to m1 receptors. Conclusions m1 Muscarinic signaling is inhibited by clinically relevant concentrations of lidocaine and by extracellularly administered QX314, suggesting that the major site of action is a extracellular domain of the muscarinic receptor. An additional less potent but superadditive inhibitory effect on the G-protein is suggested.
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Gericke, Adrian, Jan J. Sniatecki, Veronique G. A. Mayer, Evgeny Goloborodko, Andreas Patzak, Jürgen Wess, and Norbert Pfeiffer. "Role of M1, M3, and M5 muscarinic acetylcholine receptors in cholinergic dilation of small arteries studied with gene-targeted mice." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 5 (May 2011): H1602—H1608. http://dx.doi.org/10.1152/ajpheart.00982.2010.
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Acetylcholine regulates perfusion of numerous organs via changes in local blood flow involving muscarinic receptor-induced release of vasorelaxing agents from the endothelium. The purpose of the present study was to determine the role of M1, M3, and M5 muscarinic acetylcholine receptors in vasodilation of small arteries using gene-targeted mice deficient in either of the three receptor subtypes (M1R−/−, M3R−/−, or M5R−/− mice, respectively). Muscarinic receptor gene expression was determined in murine cutaneous, skeletal muscle, and renal interlobar arteries using real-time PCR. Moreover, respective arteries from M1R−/−, M3R−/−, M5R−/−, and wild-type mice were isolated, cannulated with micropipettes, and pressurized. Luminal diameter was measured using video microscopy. mRNA for all five muscarinic receptor subtypes was detected in all three vascular preparations from wild-type mice. However, M3 receptor mRNA was found to be most abundant. Acetylcholine produced dose-dependent dilation in all three vascular preparations from M1R−/−, M5R−/−, and wild-type mice. In contrast, cholinergic dilation was virtually abolished in arteries from M3R−/− mice. Deletion of either M1, M3, or M5 receptor genes did not affect responses to nonmuscarinic vasodilators, such as substance P and nitroprusside. These findings provide the first direct evidence that M3 receptors mediate cholinergic vasodilation in cutaneous, skeletal muscle, and renal interlobar arteries. In contrast, neither M1 nor M5 receptors appear to be involved in cholinergic responses of the three vascular preparations tested.
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Lai, Jiunu, Xuesi M. Shao, Richard W. Pan, Edward Dy, Cindy H. Huang, and Jack L. Feldman. "RT-PCR reveals muscarinic acetylcholine receptor mRNA in the pre-Bötzinger complex." American Journal of Physiology-Lung Cellular and Molecular Physiology 281, no. 6 (December 1, 2001): L1420—L1424. http://dx.doi.org/10.1152/ajplung.2001.281.6.l1420.
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Muscarinic receptors mediate the postsynaptic excitatory effects of acetylcholine (ACh) on inspiratory neurons in the pre-Bötzinger complex (pre-BötC), the hypothesized site for respiratory rhythm generation. Because pharmacological tools for identifying the subtypes of the muscarinic receptors that underlie these effects are limited, we probed for mRNA for these receptors in the pre-BötC. We used RT-PCR to determine the expression of muscarinic receptor subtypes in tissue punches of the pre-BötC taken from rat medullary slices. Cholinergic receptor subtype M2 and M3 mRNAs were observed in the first round of PCR amplification. All five subtypes, M1–M5, were observed in the second round of amplification. Our results suggest that the majority of muscarinic receptor subtypes in the pre-BötC are M2 and M3, with minor expression of M1, M4, and M5.
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Jiang, Shangtong, Yanfang Li, Cuilin Zhang, Yingjun Zhao, Guojun Bu, Huaxi Xu, and Yun-Wu Zhang. "M1 muscarinic acetylcholine receptor in Alzheimer’s disease." Neuroscience Bulletin 30, no. 2 (March 3, 2014): 295–307. http://dx.doi.org/10.1007/s12264-013-1406-z.
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Anju, T. R., and C. S. Paulose. "Cortical cholinergic dysregulation as a long-term consequence of neonatal hypoglycemia." Biochemistry and Cell Biology 93, no. 1 (February 2015): 47–53. http://dx.doi.org/10.1139/bcb-2014-0035.
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Neonatal hypoglycemia limits the glucose supply to cells, affecting the function of brain due to its high energy demand. This can cause long-term consequences in brain function, leading to memory and cognitive deficits. The present study evaluated the cholinergic functional regulation in cerebral cortex of one month old rats exposed to neonatal hypoglycemia to understand the long-term effects of early life stress. Receptor binding and gene expression studies were done in the cerebral cortex to analyze the changes in total muscarinicreceptors, muscarinic M1, M2, M3 receptors, and the enzymes involved in acetylcholine metabolism, cholineacetyl transferase and acetylcholine esterase. Neonatal hypoglycemia decreased total muscarinic receptors (p < 0.001) with reduced muscarinic M1, M2, and M3 receptor genes (p < 0.001) in one month old rats. The reduction in acetylcholine metabolism is indicated by the downregulated cholineacetyl transferase, upregulated acetylcholine esterase, and decreased vesicular acetylcholine transporter expression. These alterations in cholinergic function in one month old rat brain indicates the longterm consequences of neonatal hypoglycemia in cortical function, which can contribute to the onset of many disease conditions in later stages of life.
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Anju, T. R., and C. S. Paulose. "Striatal cholinergic functional alterations in hypoxic neonatal rats: Role of glucose, oxygen, and epinephrine resuscitation." Biochemistry and Cell Biology 91, no. 5 (October 2013): 350–56. http://dx.doi.org/10.1139/bcb-2012-0102.
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Molecular processes regulating cholinergic functions play an important role in the control of respiration under hypoxia. Cholinergic alterations and its further complications in respiration due to hypoxic insult in neonatal rats and the effect of glucose, oxygen, and epinephrine resuscitation was evaluated in the present study. Receptor binding and gene expression studies were done in the corpus striatum to analyse the changes in total muscarinic receptors, muscarinic M1, M2, M3 receptors, and the enzymes involved in acetylcholine metabolism, choline acetyltransferase and acetylcholinesterase. Neonatal hypoxia decreased total muscarinic receptors with reduced expression of muscarinic M1, M2, and M3 receptor genes. The reduction in acetylcholine metabolism is indicated by the downregulated choline acetyltransferase and upregulated acetyl cholinesterase expression. These cholinergic disturbances were reversed to near control in glucose-resuscitated hypoxic neonates. The adverse effects of immediate oxygenation and epinephrine administration are also reported. The present findings points to the cholinergic alterations due to neonatal hypoxic shock and suggests a proper resuscitation method to ameliorate these striatal changes.
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Santiago, Luis, and Ravinder Abrol. "Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods." International Journal of Molecular Sciences 20, no. 21 (October 24, 2019): 5290. http://dx.doi.org/10.3390/ijms20215290.
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The neurotransmitter molecule acetylcholine is capable of activating five muscarinic acetylcholine receptors, M1 through M5, which belong to the superfamily of G-protein-coupled receptors (GPCRs). These five receptors share high sequence and structure homology; however, the M1, M3, and M5 receptor subtypes signal preferentially through the Gαq/11 subset of G proteins, whereas the M2 and M4 receptor subtypes signal through the Gαi/o subset of G proteins, resulting in very different intracellular signaling cascades and physiological effects. The structural basis for this innate ability of the M1/M3/M5 set of receptors and the highly homologous M2/M4 set of receptors to couple to different G proteins is poorly understood. In this study, we used molecular dynamics (MD) simulations coupled with thermodynamic analyses of M1 and M2 receptors coupled to both Gαi and Gαq to understand the structural basis of the M1 receptor’s preference for the Gαq protein and the M2 receptor’s preference for the Gαi protein. The MD studies showed that the M1 and M2 receptors can couple to both Gα proteins such that the M1 receptor engages with the two Gα proteins in slightly different orientations and the M2 receptor engages with the two Gα proteins in the same orientation. Thermodynamic studies of the free energy of binding of the receptors to the Gα proteins showed that the M1 and M2 receptors bind more strongly to their cognate Gα proteins compared to their non-cognate ones, which is in line with previous experimental studies on the M3 receptor. A detailed analysis of receptor–G protein interactions showed some cognate-complex-specific interactions for the M2:Gαi complex; however, G protein selectivity determinants are spread over a large overlapping subset of residues. Conserved interaction between transmembrane helices 5 and 6 far away from the G-protein-binding receptor interface was found only in the two cognate complexes and not in the non-cognate complexes. An analysis of residues implicated previously in G protein selectivity, in light of the cognate and non-cognate structures, shaded a more nuanced role of those residues in affecting G protein selectivity. The simulation of both cognate and non-cognate receptor–G protein complexes fills a structural gap due to difficulties in determining non-cognate complex structures and provides an enhanced framework to probe the mechanisms of G protein selectivity exhibited by most GPCRs.
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Aihara, Takeshi, Yusuke Nakamura, Makoto M. Taketo, Minoru Matsui, and Susumu Okabe. "Cholinergically stimulated gastric acid secretion is mediated by M3 and M5 but not M1 muscarinic acetylcholine receptors in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 6 (June 2005): G1199—G1207. http://dx.doi.org/10.1152/ajpgi.00514.2004.
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Muscarinic acetylcholine receptors play an important role in the regulation of gastric acid secretion stimulated by acetylcholine; nonetheless, the precise role of each receptor subtype (M1–M5) remains unclear. This study examined the involvement of M1, M3, and M5 receptors in cholinergic regulation of acid secretion using muscarinic receptor knockout (KO) mice. Gastric acid secretion was measured in both mice subjected to acute gastric fistula production under urethane anesthesia and conscious mice that had previously undergone pylorus ligation. M3 KO mice exhibited impaired gastric acid secretion in response to carbachol. Unexpectedly, M1 KO mice exhibited normal intragastric pH, serum gastrin and mucosal histamine levels, and gastric acid secretion stimulatied by carbachol, histamine, and gastrin. Pirenzepine, known as an M1-receptor antagonist, inhibited carbachol-stimulated gastric acid secretion in a dose-dependent manner in M1 KO mice as well as in wild-type (WT) mice, suggesting that the inhibitory effect of pirenzepine on gastric acid secretion is independent of M1-receptor antagonism. Notably, M5 KO mice exhibited both significantly lower carbachol-stimulated gastric acid secretion and histamine-secretory responses to carbachol compared with WT mice. RT-PCR analysis revealed M5-mRNA expression in the stomach, but not in either the fundic or antral mucosa. Consequently, cholinergic stimulation of gastric acid secretion is clearly mediated by M3 (on parietal cells) and M5 receptors (conceivably in the submucosal plexus), but not M1 receptors.
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Swaminathan, Meyyammai, Chin Chee, Sek Chin, Michael Buckle, Noorsaadah Rahman, Stephen Doughty, and Lip Chung. "Flavonoids with M1 Muscarinic Acetylcholine Receptor Binding Activity." Molecules 19, no. 7 (June 27, 2014): 8933–48. http://dx.doi.org/10.3390/molecules19078933.
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Hulme, Edward C., and Carol A. M. Curtis. "71 Purification of recombinant M1 muscarinic acetylcholine receptor." Biochemical Society Transactions 26, no. 4 (November 1, 1998): S361. http://dx.doi.org/10.1042/bst026s361.
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Fritz, S., K. J. Föhr, S. Boddien, U. Berg, C. Brucker, and A. Mayerhofer. "Functional and Molecular Characterization of a Muscarinic Receptor Type and Evidence for Expression of Choline-Acetyltransferase and Vesicular Acetylcholine Transporter in Human Granulosa-Luteal Cells1." Journal of Clinical Endocrinology & Metabolism 84, no. 5 (May 1, 1999): 1744–50. http://dx.doi.org/10.1210/jcem.84.5.5648.
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Previously, we provided evidence for the presence of a class of muscarinic receptors on human luteinized granulosa cells (human GC) that is linked to transient increases in intracellular free calcium levels, but not to steroid production. The precise nature of the receptor is not known, and neither its function nor the source of its natural ligand acetylcholine (ACh) is clear. To address these issues we used RT-PCR approaches and isolated complementary DNAs corresponding to the M1 receptor subtype from reverse transcribed human GC messenger ribonucleic acids. M1 receptors were further shown by immunocytochemistry, using a M1 receptor antiserum. Single cell calcium measurements showed that the M1 receptor was functionally active and linked to acute increases in intracellular free calcium, as the M1 receptor specific antagonist pirenzepine blocked the Ca2+-mobilizing effect of oxotremorine M (a muscarinic agonist). An unexpected consequence of M1 receptor activation was evidenced by the ability of muscarinic agonists to stimulate the proliferation of human GC within 24 h. In vivo, ACh, the natural ligand of these receptors is thought to be contained in cholinergic nerve fibers innervating the ovary. Surprisingly, the prerequisite for the synthesis of ACh, the enzyme choline-acetyltransferase (ChAT), is also expressed by human GC, as shown by Western blotting and immunocytochemistry. In addition, these cells express another marker for ACh synthesis, namely the gene for the vesicular acetylcholine transporter, as evidenced by RT-PCR cloning, Western blotting, and immunocytochemistry. In conclusion, our data identify the M1 receptor in human GC and point to a novel, trophic role of the neurotransmitter ACh. Furthermore, the presence of the prerequisites of ACh synthesis in human GC indicate that an autocrine/paracrine regulatory loop also exists in the in vivo counterparts of these cells in the ovary, i.e. in the cells of the preovulatory follicle and/or of the young corpus luteum.
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Maeda, Shoji, Qianhui Qu, Michael J. Robertson, Georgios Skiniotis, and Brian K. Kobilka. "Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes." Science 364, no. 6440 (May 9, 2019): 552–57. http://dx.doi.org/10.1126/science.aaw5188.
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Muscarinic acetylcholine receptors are G protein–coupled receptors that respond to acetylcholine and play important signaling roles in the nervous system. There are five muscarinic receptor subtypes (M1R to M5R), which, despite sharing a high degree of sequence identity in the transmembrane region, couple to different heterotrimeric GTP-binding proteins (G proteins) to transmit signals. M1R, M3R, and M5R couple to the Gq/11 family, whereas M2R and M4R couple to the Gi/o family. Here, we present and compare the cryo–electron microscopy structures of M1R in complex with G11 and M2R in complex with GoA. The M1R-G11 complex exhibits distinct features, including an extended transmembrane helix 5 and carboxyl-terminal receptor tail that interacts with G protein. Detailed analysis of these structures provides a framework for understanding the molecular determinants of G-protein coupling selectivity.
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Durieux, Marcel E. "Halothane Inhibits Signaling through m1 Muscarinic Receptors Expressed in Xenopus Oocytes." Anesthesiology 82, no. 1 (January 1, 1995): 174–82. http://dx.doi.org/10.1097/00000542-199501000-00022.
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Background Interactions between volatile anesthetics and muscarinic acetylcholine receptors have been studied primarily in binding assays or in functional systems derived from tissues or cells, often containing multiple receptor subtypes. Because interactions with muscarinic signaling systems may explain some effects and side effects of anesthetics and form a model for anesthetic-protein interactions in general, the author studied anesthetic inhibition of muscarinic signaling in an isolated system. Methods mRNA encoding the m1 muscarinic receptor subtype was prepared in vitro and expressed in Xenopus oocytes. Effects of halothane on methylcholine-induced intracellular Ca2+ release was measured. Angiotensin II receptors were expressed to evaluate anesthetic effects on intracellular signaling. Results m1 Receptors expressed in oocytes were functional, and could be inhibited by atropine and pirenzepine. Halothane depressed m1 muscarinic signaling in a dose-dependent manner: half-maximal inhibition of 10(-7) M methylcholine was obtained with 0.3 mM halothane. The effect was reversible and could be overcome by high concentrations of muscarinic agonist. Angiotensin II signaling was unaffected by 0.34 mM halothane. Conclusions m1 Muscarinic signaling is inhibited by halothane, and lack of halothane effect on angiotensin signaling indicates that the intracellular signaling systems of Xenopus oocytes are unaffected. Therefore, the most likely site of halothane action is the receptor and/or G protein. Oocytes provide a versatile system for detailed investigation into the molecular mechanism of anesthetic-protein interactions.
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Weiden, Peter J., Samantha Yohn, and Christian C. Felder. "Understanding Why Muscarinic Receptor Agonists Have Antipsychotic Properties." CNS Spectrums 27, no. 2 (April 2022): 249. http://dx.doi.org/10.1017/s1092852922000608.
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AbstractBackgroundAll current antipsychotics have direct dopamine (DA) D2 receptor activity, which is associated with problems such as dysphoria, EPS, or prolactin elevation. Muscarinic receptor agonists have shown antipsychotic-like activity across preclinical models and clinical trials. This poster reviews preclinical evidence as to how muscarinic receptor agonists, such as the M1/M4 preferring agonist xanomeline, might have clinically relevant antipsychotic effects.ObjectivesHighlight the novel mechanisms through which muscarinic receptor agonists are associated with antipsychotic effects without having any direct dopaminergic D2 receptor activity.Key PointsThe muscarinic receptor family is composed of 5 G protein-coupled receptors (GPCRs). One of the leading hypotheses explaining the antipsychotic activity of muscarinic receptor agonists is preclinical studies of muscarinic receptor modulation of those DA circuits associated with psychosis. Both M1 and M4 receptors are expressed in DA neural circuits implicated in psychosis, and provide unique regulation of these circuits. Xanomeline has both functional M1 and M4 receptor agonist activity, and shows robust antipsychotic-like effects in several animal models that require the presence of functional M1 and M4 receptors. M4 receptors are autoreceptors on cholinergic neurons that regulate DA circuits in two locations: ventral tegmental area (VTA) and nucleus accumbens (NAc). Cholinergic-rich neurons from the hindbrain at the VTA, where they release acetylcholine (ACh) into DA-rich synaptic spaces. M4 autoreceptors are present on these neurons, and their activation reduces ACh release and lowers ambient synaptic ACh concentrations, leading to reduced DA cell firing. Cholinergic interneurons residing in the NAc also express M4 autoreceptors. These ACh interneurons regulate ACh release with M4 activation also turning off ACh release. Therefore, M4 receptors serve as DA regulators at VTA and NAc, both key sites for dopamine’s role in psychotic processes. M1 receptors regulate DA circuits in a different, “top down” manner. M1 receptors are found on cortical inhibitory interneurons. When activated, inhibitory drive onto excitatory output neurons is enhanced, which leads to reduced excitatory tone to VTA DA neurons.SummaryOver the last 25 years, a growing body of evidence has shown potential for muscarinic receptor agonists to become a new class of medicines with potent antipsychotic activity. Preclinical data at micro-and macro-circuit levels suggest that the M1 and M4 receptor subtypes are most relevant in the regulation of DA circuits. The antipsychotic effects of muscarinic agonists effects may arise from influencing these key muscarinic receptor subtypes that are integral to the regulation of DA neural circuits. In summary, there has been great progress in understanding the potential for muscarinic receptor agonists for the treatment of psychosis.FundingKaruna Therapeutics
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Hedrick, Tristan, and Jack Waters. "Acetylcholine excites neocortical pyramidal neurons via nicotinic receptors." Journal of Neurophysiology 113, no. 7 (April 2015): 2195–209. http://dx.doi.org/10.1152/jn.00716.2014.
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The neuromodulator acetylcholine (ACh) shapes neocortical function during sensory perception, motor control, arousal, attention, learning, and memory. Here we investigate the mechanisms by which ACh affects neocortical pyramidal neurons in adult mice. Stimulation of cholinergic axons activated muscarinic and nicotinic ACh receptors on pyramidal neurons in all cortical layers and in multiple cortical areas. Nicotinic receptor activation evoked short-latency, depolarizing postsynaptic potentials (PSPs) in many pyramidal neurons. Nicotinic receptor-mediated PSPs promoted spiking of pyramidal neurons. The duration of the increase in spiking was membrane potential dependent, with nicotinic receptor activation triggering persistent spiking lasting many seconds in neurons close to threshold. Persistent spiking was blocked by intracellular BAPTA, indicating that nicotinic ACh receptor activation evoked persistent spiking via a long-lasting calcium-activated depolarizing current. We compared nicotinic PSPs in primary motor cortex (M1), prefrontal cortex (PFC), and visual cortex. The laminar pattern of nicotinic excitation was not uniform but was broadly similar across areas, with stronger modulation in deep than superficial layers. Superimposed on this broad pattern were local differences, with nicotinic PSPs being particularly large and common in layer 5 of M1 but not layer 5 of PFC or primary visual cortex (V1). Hence, in addition to modulating the excitability of pyramidal neurons in all layers via muscarinic receptors, synaptically released ACh preferentially increases the activity of deep-layer neocortical pyramidal neurons via nicotinic receptors, thereby adding laminar selectivity to the widespread enhancement of excitability mediated by muscarinic ACh receptors.
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Crans, René Albert Johan. "Heterodimerization between dopamine D2 receptor and M1 muscarinic acetylcholine receptor." Intrinsic Activity 4, Suppl. 2 (August 29, 2016): A18.1. http://dx.doi.org/10.25006/ia.4.s2-a18.1.
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Ma, Lei, Matthew A. Seager, Marion Wittmann, Marlene Jacobson, Denise Bickel, Maryann Burno, Keith Jones, et al. "Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation." Proceedings of the National Academy of Sciences 106, no. 37 (August 26, 2009): 15950–55. http://dx.doi.org/10.1073/pnas.0900903106.
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The forebrain cholinergic system promotes higher brain function in part by signaling through the M1 muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M1 receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M1 mAChR. BQCA reduces the concentration of ACh required to activate M1 up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 μM. Furthermore studies in M1−/− mice demonstrates that BQCA requires M1 to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M1 allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces β-arrestin recruitment to M1, suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M1 receptor and represents a promising therapeutic strategy for cognitive disorders.
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Yang, Jyh-Jeen, Yu-Ting Wang, Pi-Cheng Cheng, Yeh-Jung Kuo, and Rong-Chi Huang. "Cholinergic Modulation of Neuronal Excitability in the Rat Suprachiasmatic Nucleus." Journal of Neurophysiology 103, no. 3 (March 2010): 1397–409. http://dx.doi.org/10.1152/jn.00877.2009.
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The central cholinergic system regulates both the circadian clock and sleep-wake cycle and may participate in the feedback control of vigilance states on neural excitability in the suprachiasmatic nucleus (SCN) that houses the circadian clock. Here we investigate the mechanisms for cholinergic modulation of SCN neuron excitability. Cell-attached recordings indicate that the nonspecific cholinergic agonist carbachol (CCh) inhibited 55% and excited 21% SCN neurons, leaving 24% nonresponsive. Similar response proportions were produced by two muscarinic receptor [muscarinic acetylcholine receptor (mAChR)] agonists, muscarine and McN-A-343 (M1/4 agonist), but not by two nicotinic receptor (nAChR) agonists, nicotine and choline (α7-nAChR agonist), which, however, produced similar response proportions. Whole cell and perforated-patch recordings indicate that CCh inhibition of firing was mediated by membrane hyperpolarization due to activation of background K+ currents, which were sensitive to submillimolar concentrations of Ba2+ and to millimolar concentrations of TEA. RT-PCR analysis demonstrated the presence of mRNA for M1 to M5 mAChRs in SCN. The CCh-induced hyperpolarization and activation of background K+ currents were blocked by M4 antagonists and to a lesser degree by M1 antagonists but were insensitive to the antagonists for M2 or M3, suggesting the involvement of M4 and M1 mAChRs in mediating CCh inhibition of firing. CCh enhancement of firing was mediated by membrane depolarization, as a result of postsynaptic inhibition of background K+ currents. The multiple actions of cholinergic modulation via multiple receptors and ion channels may allow acetylcholine to finely control SCN neuron excitability in different physiological settings.
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Takamori, M., M. Motomura, T. Fukudome, and H. Yoshikawa. "Autoantibodies against M1 muscarinic acetylcholine receptor in myasthenic disorders." European Journal of Neurology 14, no. 11 (November 2007): 1230–35. http://dx.doi.org/10.1111/j.1468-1331.2007.01931.x.
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Lee, N. H., and C. M. Fraser. "Post-transcriptional regulation of the m1 muscarinic acetylcholine receptor." Life Sciences 52, no. 5-6 (January 1993): 562. http://dx.doi.org/10.1016/0024-3205(93)90340-9.
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Strang, Christianne E., Ye Long, Konstantin E. Gavrikov, Franklin R. Amthor, and Kent T. Keyser. "Nicotinic and muscarinic acetylcholine receptors shape ganglion cell response properties." Journal of Neurophysiology 113, no. 1 (January 1, 2015): 203–17. http://dx.doi.org/10.1152/jn.00405.2014.
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The purpose of this study was to evaluate the expression patterns of nicotinic and muscarinic ACh receptors (nAChRs and mAChRs, respectively) in relation to one another and to understand their effects on rabbit retinal ganglion cell response properties. Double-label immunohistochemistry revealed labeled inner-retinal cell bodies and complex patterns of nAChR and mAChR expression in the inner plexiform layer. Specifically, the expression patterns of m1, m4, and m5 muscarinic receptors overlapped with those of non-α7 and α7 nicotinic receptors in presumptive amacrine and ganglion cells. There was no apparent overlap in the expression patterns of m2 muscarinic receptors with α7 nicotinic receptors or of m3 with non-α7 nicotinic receptors. Patch-clamp recordings demonstrated cell type-specific effects of nicotinic and muscarinic receptor blockade. Muscarinic receptor blockade enhanced the center responses of brisk-sustained/G4 On and G4 Off ganglion cells, whereas nicotinic receptor blockade suppressed the center responses of G4 On-cells near the visual streak but enhanced the center responses of nonstreak G4 On-cells. Blockade of muscarinic or nicotinic receptors suppressed the center responses of brisk-sustained Off-cells and the center light responses of subsets of brisk-transient/G11 On- and Off-cells. Only nicotinic blockade affected the center responses of G10 On-cells and G5 Off-cells. These data indicate that physiologically and morphologically identified ganglion cell types have specific patterns of AChR expression. The cholinergic receptor signatures of these cells may have implications for understanding visual defects in disease states that result from decreased ACh availability.
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Takeuchi, Tadayoshi, Kaori Fujinami, Hiroto Goto, Akikazu Fujita, Makoto M. Taketo, Toshiya Manabe, Minoru Matsui, and Fumiaki Hata. "Roles of M2 and M4 Muscarinic Receptors in Regulating Acetylcholine Release From Myenteric Neurons of Mouse Ileum." Journal of Neurophysiology 93, no. 5 (May 2005): 2841–48. http://dx.doi.org/10.1152/jn.00986.2004.
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We investigated the subtype of presynaptic muscarinic receptors associated with inhibition of acetylcholine (ACh) release in the mouse small intestine. We measured endogenous ACh released from longitudinal muscle with myenteric plexus (LMMP) preparations obtained from M1–M5 receptor knockout (KO) mice. Electrical field stimulation (EFS) increased ACh release in all LMMP preparations obtained from M1–M5 receptor single KO mice. The amounts of ACh released in all preparations were equal to that in the wild-type mice. Atropine further increased EFS-induced ACh release in the wild-type mice. Unexpectedly, atropine also increased, to a similar extent, EFS-induced ACh release to the wild-type mice in all M1–M5 receptor single KO mice. In M2 and M4 receptor double KO mice, the amount of EFS-induced ACh release was equivalent to an atropine-evoked level in the wild-type mouse, and further addition of atropine had no effect. M2 receptor immunoreactivity was located in both smooth muscle cells and enteric neurons. M4 receptor immunoreactivity was located in the enteric neurons, being in co-localization with M2 receptor immunoreactivity. These results indicate that both M2 and M4 receptors mediate the muscarinic autoinhibition in ACh release in the LMMP preparation of the mouse ileum, and loss of one of these subtypes can be compensated functionally by a receptor that remained. M1, M3, and M5 receptors do not seem to be involved in this mechanism.
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Hildebrandt, J. P., and T. J. Shuttleworth. "Muscarinic receptor characterization in differentiating avian exocrine cells." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 266, no. 3 (March 1, 1994): R674—R681. http://dx.doi.org/10.1152/ajpregu.1994.266.3.r674.
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The type of muscarinic acetylcholine receptor in exocrine cells of the avian nasal gland in the undifferentiated quiescent (naive) stage and in the partly differentiated salt-secreting (stressed) stage was characterized by ligand binding experiments and by probing receptor messenger RNA with oligonucleotide probes specific for the mammalian receptor subtypes. Competition-binding studies using l-quinuclidinyl [phenyl-4-3H]benzilate and a series of other ligands indicated the presence of only one type of receptor in both cell types. Pharmacological characterization of its ligand-binding properties revealed similarities with the mammalian M3 type. However, 4-[[[(3-chlorophenyl)amino]carbonyl]oxy]-N,N,N-trimethyl-2-butyn-1 - aminium chloride, generally a partial agonist in cells expressing mammalian M1 receptors, released calcium from intracellular stores in naive and stressed cells. To resolve this, we attempted to characterize the salt gland receptor by molecular means. Northern analysis of salt gland mRNA revealed weak signals only with oligonucleotide probes corresponding to the mammalian m1 receptor type. However, at higher stringencies these signals faded, indicating that the salt gland receptor may resemble the mammalian m1 subtype but has probably a considerable degree of sequence divergence. Such divergence may also explain the observed differences in pharmacological behavior between the avian and the mammalian glandular receptors.
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Boschero, A. C., M. Szpak-Glasman, E. M. Carneiro, S. Bordin, I. Paul, E. Rojas, and I. Atwater. "Oxotremorine-m potentiation of glucose-induced insulin release from rat islets involves M3 muscarinic receptors." American Journal of Physiology-Endocrinology and Metabolism 268, no. 2 (February 1, 1995): E336—E342. http://dx.doi.org/10.1152/ajpendo.1995.268.2.e336.
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cDNAs encoding for M1 and M3 muscarinic acetylcholine (ACh) receptors were detected in rat pancreatic islet cells by polymerase chain reaction (PCR) amplification techniques. A new cholinergic agonist, oxotremorine-m (oxo-m), in the presence of glucose (5.6 mM), produced a dose-dependent potentiation of insulin secretion saturating at approximately 5 microM. This effect was suppressed by the L-type Ca2+ channel blocker nifedipine. Higher doses of oxo-m (50 microM) induced a biphasic insulin response both at low (5.6 mM) or high (16.7 mM) glucose concentrations. In a Ca(2+)-deficient medium containing glucose (5.6 mM), oxo-m evoked only a reduced first phase of insulin secretion. The potentiating effects of oxo-m were inhibited by the muscarinic receptor antagonists 4-diphenylacetoxy-N-methylpiperidine methiodide (M3), hexahydro-sila-difenidol hydrochloride, p-fluoro analogue (M3 > M1 > M2), and pirenzepine (M1) in a dose-dependent manner; half-maximal inhibitory concentration values were approximately 5, 20, and 340 nM, respectively. The PCR results demonstrate the presence of M1 and M3 muscarinic ACh receptors in the islet tissue, and the secretion data strongly suggest that the potentiation of glucose-induced insulin release evoked by oxo-m depends on the activation of a muscarinic M3-subtype receptor present in the beta-cell membrane.
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Louie, D. S., and C. Owyang. "Muscarinic receptor subtypes on rat pancreatic acini: secretion and binding studies." American Journal of Physiology-Gastrointestinal and Liver Physiology 251, no. 2 (August 1, 1986): G275—G279. http://dx.doi.org/10.1152/ajpgi.1986.251.2.g275.
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Characterization of muscarinic receptor subtypes on rat pancreatic acinar cells was examined by using specific muscarinic receptor antagonists to study amylase secretion and binding of [N-methyl-3H]scopolamine ([3H]NMS). Rat pancreatic acini were dispersed in HEPES-Ringer buffer and incubated with acetylcholine +/- 4-diphenylacetoxy-N-methylpiperadine-methiodide (4-DAMP, a specific M2 muscarinic receptor antagonist) or +/- pirenzepine (a specific M1 muscarinic receptor antagonist). 4-DAMP (10(-9) to 10(-6) M) caused a progressive parallel rightward shift in the acetylcholine dose-response curve without a change in maximal amylase release. Only high concentrations of pirenzepine (10(-6) to 10(-4) M) caused a rightward shift in the dose-response curve to acetylcholine. Schild analysis of the data indicated an inhibitory constant (Ki) of 200 pM for 4-DAMP and 183 nM for pirenzepine. The slope of the Schild regression lines was not different from unity, suggesting competitive inhibition. Binding of 50 pM [3H]NMS was specific, rapid, and saturable. [3H]NMS binding was displaced by increasing concentrations of 4-DAMP or pirenzepine with apparent Ki's of 102 pM and 330 nM, respectively, and similar maximal binding levels of 60 fmol/mg prot. We have demonstrated that 4-DAMP has an approximately 1,000-fold greater potency than pirenzepine to inhibit amylase release and binding, indicating that cholinergic-stimulated amylase release from pancreatic acini is mediated by M2 muscarinic receptors.
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Elhusseiny, Ahmed, Zvi Cohen, André Olivier, Danica B. Stanimirović, and Edith Hamel. "Functional Acetylcholine Muscarinic Receptor Subtypes in Human Brain Microcirculation: Identification and Cellular Localization." Journal of Cerebral Blood Flow & Metabolism 19, no. 7 (July 1999): 794–802. http://dx.doi.org/10.1097/00004647-199907000-00010.
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Acetylcholine is an important regulator of local cerebral blood flow. There is, however, limited information available on the possible sites of action of this neurotransmitter on brain intraparenchymal microvessels. In this study, a combination of molecular and functional approaches was used to identify which of the five muscarinic acetylcholine receptors (mAChR) are present in human brain microvessels and their intimately associated astroglial cells. Microvessel and capillary fractions isolated from human cerebral cortex were found by reverse transcriptase-polymerase chain reaction to express m2, m3, and, occasionally, m1 and m5 receptor subtypes. To localize these receptors to a specific cellular compartment of the vessel wall, cultures of human brain microvascular endothelial and smooth muscle cells were used, together with cultured human brain astrocytes. Endothelial cells invariably expressed m2 and m5 receptors, and occasionally the m1 receptor; smooth muscle cells exhibited messages for all except the m4 mAChR subtypes, whereas messages for all five muscarinic receptors were identified in astrocytes. In all three cell types studied, acetylcholine induced a pirenzepine-sensitive increase (62% to 176%, P < 0.05 to 0.01) in inositol trisphosphate, suggesting functional coupling of m1, m3, or m5 mAChR to a phospholipase C signaling cascade. Similarly, coupling of m2 or m4 mAChR to adenylate cyclase inhibition in endothelial cells and astrocytes, but not in smooth muscle cells, was demonstrated by the ability of carbachol to significantly reduce (44% to 50%, P < 0.05 to 0.01) the forskolin-stimulated increase in cAMP levels. This effect was reversed by the mAChR antagonist AF-DX 384. The results indicate that microvessels are able to respond to neurally released acetylcholine and that mAChR, distributed in different vascular and astroglial compartments, could regulate cortical perfusion and, possibly, blood–brain barrier permeability, functions that could become jeopardized in neurodegenerative disorders such as Alzheimer's disease.
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Hyman, A. L., and P. J. Kadowitz. "Tone-dependent responses to acetylcholine in the feline pulmonary vascular bed." Journal of Applied Physiology 64, no. 5 (May 1, 1988): 2002–9. http://dx.doi.org/10.1152/jappl.1988.64.5.2002.
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The effects of an increase in base-line tone on pulmonary vascular responses to acetylcholine were investigated in the pulmonary vascular bed of the intact-chest cat. Under conditions of controlled blood flow and constant left atrial pressure, intralobar injections of acetylcholine under low-tone base-line conditions increased lobar arterial pressure in a dose-related manner. When tone was increased moderately by alveolar hypoxia, acetylcholine elicited dose-dependent decreases in lobar arterial pressure, and at the highest dose studied, acetylcholine produced a biphasic response. When tone was raised to a high steady level with the prostaglandin analogue, U46619, acetylcholine elicited marked dose-related decreases in lobar arterial pressure. Atropine blocked both vasoconstrictor responses at low tone and vasodilator responses at high tone, whereas meclofenamate and BW 755C had no effect on responses to acetylcholine at low or high tone. The vasoconstrictor response at low tone was blocked by pirenzepine (20 and 50 micrograms/kg iv) but not gallamine (10 mg/kg iv). The vasodilator response at high tone was not blocked by pirenzepine (50 micrograms/kg iv) or gallamine or pancuronium (10 mg/kg iv). The present data support the concept that pulmonary vascular responses to acetylcholine are tone dependent and suggest that the vasoconstrictor response under low-tone conditions is mediated by a high-affinity muscarinic (M1)-type receptor. These data also suggest that vasodilator responses under high-tone conditions are mediated by muscarinic receptors that are neither M1 nor M2 low-affinity muscarinic-type receptor and that responses to acetylcholine are not dependent on the release of cyclooxygenase or lipoxygenase products.
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Maeda, Shoji, Jun Xu, Francois Marie N. Kadji, Mary J. Clark, Jiawei Zhao, Naotaka Tsutsumi, Junken Aoki, et al. "Structure and selectivity engineering of the M1 muscarinic receptor toxin complex." Science 369, no. 6500 (July 9, 2020): 161–67. http://dx.doi.org/10.1126/science.aax2517.
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Muscarinic toxins (MTs) are natural toxins produced by mamba snakes that primarily bind to muscarinic acetylcholine receptors (MAChRs) and modulate their function. Despite their similar primary and tertiary structures, MTs show distinct binding selectivity toward different MAChRs. The molecular details of how MTs distinguish MAChRs are not well understood. Here, we present the crystal structure of M1AChR in complex with MT7, a subtype-selective anti-M1AChR snake venom toxin. The structure reveals the molecular basis of the extreme subtype specificity of MT7 for M1AChR and the mechanism by which it regulates receptor function. Through in vitro engineering of MT7 finger regions that was guided by the structure, we have converted the selectivity from M1AChR toward M2AChR, suggesting that the three-finger fold is a promising scaffold for developing G protein–coupled receptor modulators.
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Chang, Wenhan, Tsui-Hua Chen, Stacy A. Pratt, Benedict Yen, Michael Fu, and Dolores Shoback. "Parathyroid Ca2+-conducting currents are modulated by muscarinic receptor agonists and antagonists." American Journal of Physiology-Endocrinology and Metabolism 273, no. 5 (November 1, 1997): E880—E890. http://dx.doi.org/10.1152/ajpendo.1997.273.5.e880.
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Parathyroid cells express Ca2+-conducting cation currents, which are activated by raising the extracellular Ca2+ concentration ([Ca2+]o) and blocked by dihydropyridines. We found that acetylcholine (ACh) inhibited these currents in a reversible, dose-dependent manner (50% inhibitory concentration ≈10−8 M). The inhibitory effects could be mimicked by the agonist (+)-muscarine. The effects of ACh were blunted by the antagonist atropine and reversed by removing ATP from the pipette solution. (+)-Muscarine enhanced the adenosine 3′,5′-cyclic monophosphate (cAMP) production by 30% but had no effect on inositol phosphate accumulation in parathyroid cells. Oligonucleotide primers, based on sequences of known muscarinic receptors (M1-M5), were used in reverse transcriptase-polymerase chain reaction (RT-PCR) to amplify receptor cDNA from parathyroid poly (A)+ RNA. RT-PCR products displayed >90% nucleotide sequence identity to human M2- and M4-receptor cDNAs. Expression of M2-receptor protein was further confirmed by immunoblotting and immunocytochemistry. Thus parathyroid cells express muscarinic receptors of M2 and possibly M4 subtypes. These receptors may couple to dihydropyridine-sensitive, cation-selective currents through the activation of adenylate cyclase and ATP-dependent pathways in these cells.
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Shmuel, Miriam, Efrat Nodel-Berner, Tehila Hyman, Alexander Rouvinski, and Yoram Altschuler. "Caveolin 2 Regulates Endocytosis and Trafficking of the M1 Muscarinic Receptor in MDCK Epithelial Cells." Molecular Biology of the Cell 18, no. 5 (May 2007): 1570–85. http://dx.doi.org/10.1091/mbc.e06-07-0618.
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Clathrin and caveolins are known for their involvement in the internalization of numerous receptors. Here we show that in polarized epithelial Madin-Darby canine kidney cells, both the clathrin machinery and caveolins are involved in the endocytosis and delivery to the plasma membrane (PM) of the M1 muscarinic acetylcholine receptor (mAChR). We initially localized this receptor to the lateral membrane, where it accumulates proximal to the tight junctions. From there it is internalized through the clathrin-mediated pathway. In addition, the receptor may associate on the PM with caveolin (cav) 2 or in intracellular compartments with either cav 2, or monomeric or oligomeric cav 1. Association of the PM M1 mAChR with cav 2 inhibits receptor endocytosis through the clathrin-mediated pathway or retains the receptor in an intracellular compartment. This intracellular association attenuates receptor trafficking. Expression of cav 1 with cav 2 rescues the latter's inhibitory effect. The caveolins stimulate M1 mAChR oligomerization thus maintaining a constant amount of monomeric receptor. These results provide evidence that caveolins play a role in the attenuation of the M1 muscarinic receptor's intracellular trafficking to and from the PM.
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Marcé‐Grau, Anna, Xabier Elorza‐Vidal, Carla Pérez‐Rius, Anna Ruiz‐Nel·lo, Júlia Sala‐Coromina, Elisabet Gabau, Raúl Estévez, and Alfons Macaya. "Muscarinic acetylcholine receptor M1 mutations causing neurodevelopmental disorder and epilepsy." Human Mutation 42, no. 10 (July 10, 2021): 1215–20. http://dx.doi.org/10.1002/humu.24252.
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Anagnostaras, Stephan G., Geoffrey G. Murphy, Susan E. Hamilton, Scott L. Mitchell, Nancy P. Rahnama, Neil M. Nathanson, and Alcino J. Silva. "Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice." Nature Neuroscience 6, no. 1 (December 16, 2002): 51–58. http://dx.doi.org/10.1038/nn992.
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Sawatzky, Deborah A., Paul J. Kingham, Niamh Durcan, W. Graham McLean, and Richard W. Costello. "Eosinophil-induced release of acetylcholine from differentiated cholinergic nerve cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 285, no. 6 (December 2003): L1296—L1304. http://dx.doi.org/10.1152/ajplung.00107.2003.
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One immunological component of asthma is believed to be the interaction of eosinophils with parasympathetic cholinergic nerves and a consequent inhibition of acetylcholine muscarinic M2 receptor activity, leading to enhanced acetylcholine release and bronchoconstriction. Here we have used an in vitro model of cholinergic nerve function, the human IMR32 cell line, to study this interaction. IMR32 cells, differentiated in culture for 7 days, expressed M2 receptors. Cells were radiolabeled with [3H]choline and electrically stimulated. The stimulation-induced release of acetylcholine was prevented by the removal of Ca2+. The muscarinic M1/M2 receptor agonist arecaidine reduced the release of acetylcholine after stimulation (to 82 ± 2% of control at 10-7 M), and the M2 receptor antagonist AF-DX 116 increased it (to 175 ± 23% of control at 10-5 M), indicating the presence of a functional M2 receptor that modulated acetylcholine release. When human eosinophils were added to IMR32 cells, they enhanced acetylcholine release by 36 ± 10%. This effect was prevented by inhibitors of adhesion of the eosinophils to the IMR32 cells. Pretreatment of IMR32 cells with 10 mM carbachol, to desensitize acetylcholine receptors, prevented the potentiation of acetylcholine release by eosinophils or AF-DX 116. Acetylcholine release was similarly potentiated (by up to 45 ± 7%) by degranulation products from eosinophils that had been treated with N-formyl-methionyl-leucyl-phenylalanine or that had been in contact with IMR32 cells. Contact between eosinophils and IMR32 cells led to an initial increase in expression of M2 receptors, whereas prolonged exposure reduced M2 receptor expression.
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Olianas, Maria C., Carlo Maullu, Abdu Adem, Ezra Mulugeta, Evert Karlsson, and Pierluigi Onali. "Inhibition of acetylcholine muscarinic M1 receptor function by the M1 -selective ligand muscarinic toxin 7 (MT-7)." British Journal of Pharmacology 131, no. 3 (October 2000): 447–52. http://dx.doi.org/10.1038/sj.bjp.0703606.
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Janossy, A., E. Orso, KS Szalay, Z. Juranyi, M. Beck, ES Vizi, and GP Vinson. "Cholinergic regulation of the rat adrenal zona glomerulosa." Journal of Endocrinology 157, no. 2 (May 1, 1998): 305–15. http://dx.doi.org/10.1677/joe.0.1570305.
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Using histochemical and immunocytochemical methods, cholinergic nerve fibres were demonstrated in the rat adrenal cortex, primarily in the capsule and zona glomerulosa, and in the medulla. Some terminated among the glomerulosa cells or around blood vessels. Occasional fibres were also seen in the fasciculata, ending in islets of chromaffin tissue without ramifications on cortical cells. To clarify the role of cholinergic innervation, a microvolume perifusion system was used to study steroid production by the rat adrenal capsule-glomerulosa. Acetylcholine (ACh) itself had no reproducible effects; however, since variable amounts of endogenous ACh were present, the actions of antagonists were also studied. The M1 muscarinic receptor antagonist pirenzepine (10 and 100 microM) stimulated aldosterone secretion. This stimulation was abolished by co-incubation with carbachol, the M1 agonist McN A-343 and by atropine. We found that the action of pirenzepine was blocked by nifedipine (Ca2+ channel blocker), suggesting that pirenzepine (through release of endogenous ACh) provides an acute stimulus by enhancing Ca2+ inflow. Hemicholine, a choline uptake blocker, reduced the stimulatory effect of pirenzepine on steroid secretion, confirming that stimulation was of neural origin. Neither the non-selective muscarinic receptor antagonist atropine, the selective M1-M3 muscarinic receptor antagonist 4-DAMP, nor the selective M2 muscarinic receptor antagonist methoctramine influenced aldosterone output. Receptor-binding studies revealed the existence of M3 receptors in capsule-glomerulosa homogenates. We conclude that pirenzepine acts on presynaptic M1 autoreceptors to increase spontaneous ACh release from varicose axon terminals that lie in close proximity to the glomerulosa cells. In turn ACh may thus stimulate steroidogenesis acutely through M3 receptors. These results support the concept of a direct cholinergic influence on zona glomerulosa function in the rat.
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Nissen, Christoph, Ann E. Power, Eric A. Nofzinger, Bernd Feige, Ulrich Voderholzer, Corinna Kloepfer, Bernhard Waldheim, Marc-Philipp Radosa, Mathias Berger, and Dieter Riemann. "M1 Muscarinic Acetylcholine Receptor Agonism Alters Sleep without Affecting Memory Consolidation." Journal of Cognitive Neuroscience 18, no. 11 (November 2006): 1799–807. http://dx.doi.org/10.1162/jocn.2006.18.11.1799.
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Preclinical studies have implicated cholinergic neurotransmission, specifically M1 muscarinic acetylcholine receptor (mAChR) activation, in sleep-associated memory consolidation. In the present study, we investigated the effects of administering the direct M1 mAChR agonist RS-86 on pre-post sleep memory consolidation. Twenty healthy human participants were tested in a declarative word-list task and a procedural mirror-tracing task. RS-86 significantly reduced rapid eye movement (REM) sleep latency and slow wave sleep (SWS) duration in comparison with placebo. Presleep acquisition and postsleep recall rates were within the expected ranges. However, recall rates in both tasks were almost identical for the RS-86 and placebo conditions. These results indicate that selective M1 mAChR activation in healthy humans has no clinically relevant effect on pre-post sleep consolidation of declarative or procedural memories at a dose that reduces REM sleep latency and SWS duration.
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Kato, Mihoko, Irina Kolotuev, Alexandre Cunha, Shahla Gharib, and Paul W. Sternberg. "Extrasynaptic acetylcholine signaling through a muscarinic receptor regulates cell migration." Proceedings of the National Academy of Sciences 118, no. 1 (December 23, 2020): e1904338118. http://dx.doi.org/10.1073/pnas.1904338118.
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Acetylcholine (ACh) promotes various cell migrations in vitro, but there are few investigations into this nonsynaptic role of ACh signaling in vivo. Here we investigate the function of a muscarinic receptor on an epithelial cell migration in Caenorhabditis elegans. We show that the migratory gonad leader cell, the linker cell (LC), uses an M1/M3/M5-like muscarinic ACh receptor GAR-3 to receive extrasynaptic ACh signaling from cholinergic neurons for its migration. Either the loss of the GAR-3 receptor in the LC or the inhibition of ACh release from cholinergic neurons resulted in migratory path defects. The overactivation of the GAR-3 muscarinic receptor caused the LC to reverse its orientation through its downstream effectors Gαq/egl-30, PLCβ/egl-8, and TRIO/unc-73. This reversal response only occurred in the fourth larval stage, which corresponds to the developmental time when the GAR-3::yellow fluorescent protein receptor in the membrane relocalizes from a uniform to an asymmetric distribution. These findings suggest a role for the GAR-3 muscarinic receptor in determining the direction of LC migration.
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Mitchell, F. M., M. Russell, and G. L. Johnson. "Differential calcium dependence in the activation of c-Jun kinase and mitogen-activated protein kinase by muscarinic acetylcholine receptors in rat 1a cells." Biochemical Journal 309, no. 2 (July 15, 1995): 381–84. http://dx.doi.org/10.1042/bj3090381.
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Carbachol stimulation of the muscarinic acetylcholine m1 receptor (m1R), stably expressed in Rat 1a fibroblasts, resulted in a calcium-dependent activation of c-Jun kinase (JNK). Stimulation of the muscarinic acetylcholine m2 receptor (m2R), stably expressed in Rat 1a fibroblasts, resulted in a G1-mediated activation of JNK that was weak relative to that observed with the m1R. Chelation of calcium inhibited the m2R-mediated activation of JNK but not the robust m2R stimulation of mitogen-activated protein kinase (MAPK) activity. These findings demonstrate a role for the second messenger, calcium, in the differential regulation of the activity of JNK and MAPK in Rat 1a cells.
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Nadal, Laura, Neus Garcia, Erica Hurtado, Anna Simó, Marta Tomàs, Maria Angel Lanuza, Victor Cilleros, and Josep Maria Tomàs. "Synergistic Action of Presynaptic Muscarinic Acetylcholine Receptors and Adenosine Receptors in Developmental Axonal Competition at the Neuromuscular Junction." Developmental Neuroscience 38, no. 6 (2016): 407–19. http://dx.doi.org/10.1159/000458437.
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The development of the nervous system involves the initial overproduction of synapses, which promotes connectivity. Hebbian competition between axons with different activities leads to the loss of roughly half of the overproduced elements and this refines connectivity. We used quantitative immunohistochemistry to investigate, in the postnatal day 7 (P7) to P9 neuromuscular junctions, the involvement of muscarinic receptors (muscarinic acetylcholine autoreceptors and the M1, M2, and M4 subtypes) and adenosine receptors (A1 and A2A subtypes) in the control of axonal elimination after the mouse levator auris longus muscle had been exposed to selective antagonists in vivo. In a previous study we analyzed the role of each of the individual receptors. Here we investigate the additive or occlusive effects of their inhibitors and thus the existence of synergistic activity between the receptors. The main results show that the A2A, M1, M4, and A1 receptors (in this order of ability) delayed axonal elimination at P7. M4 produces some occlusion of the M1 pathway and some addition to the A1 pathway, which suggests that they cooperate. M2 receptors may modulate (by allowing a permissive action) the other receptors, mainly M4 and A1. The continued action of these receptors (now including M2 but not M4) finally promotes axonal loss at P9. All 4 receptors (M2, M1, A1, and A2A, in this order of ability) are necessary. The M4 receptor (which in itself does not affect axon loss) seems to modulate the other receptors. We found a synergistic action between the M1, A1, and A2A receptors, which show an additive effect, whereas the potent M2 effect is largely independent of the other receptors (though can be modulated by M4). At P9, there is a full mutual dependence between the A1 and A2A receptors in regulating axon loss. In summary, postnatal axonal elimination is a regulated multireceptor mechanism that involves the cooperation of several muscarinic and adenosine receptor subtypes.
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Fitzgerald, Robert S., Machiko Shirahata, and Tohru Ide. "Further cholinergic aspects of carotid body chemotransduction of hypoxia in cats." Journal of Applied Physiology 82, no. 3 (March 1, 1997): 819–27. http://dx.doi.org/10.1152/jappl.1997.82.3.819.
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Fitzgerald, Robert S., Machiko Shirahata, and Tohru Ide.Further cholinergic aspects of carotid body chemotransduction of hypoxia in cats. J. Appl. Physiol.82(3): 819–827, 1997.—From the 1930s into the 1970s, the role of acetylcholine (ACh) in the carotid body’s chemotransduction of hypoxia was debated. Since the late 1970s, the issue has been pursued only intermittently or not at all. The purpose of this study was to test again with a new preparation the hypothesis that ACh is an excitatory neurotransmitter in the cat carotid body’s chemotransduction of hypoxia. We tested the effect of the specific nicotinic blocker mecamylamine and the muscarinic blocker of all five muscarinic receptors, atropine. We further tested the effects of M1 and M2 muscarinic-receptor blockers. The carotid body region was selectively perfused with hypoxic Krebs-Ringer bicarbonate (KRB) solutions that were blocker free or contained varying doses of the blockers. Both mecamylamine and atropine reduced the response to hypoxic KRB in a dose-related manner. The M2 muscarinic-receptor blockers gallamine and AFDX 116 increased the response to hypoxic KRB, whereas the M1 muscarinic-receptor blocker pirenzepine reduced the response to hypoxic KRB. These data are consistent with an excitatory role for ACh in the carotid body chemotransduction of hypoxia in the cat.
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Kullmann, F. Aura, D. Artim, J. Beckel, S. Barrick, W. C. de Groat, and L. A. Birder. "Heterogeneity of muscarinic receptor-mediated Ca2+ responses in cultured urothelial cells from rat." American Journal of Physiology-Renal Physiology 294, no. 4 (April 2008): F971—F981. http://dx.doi.org/10.1152/ajprenal.00313.2007.
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Muscarinic receptors (mAChRs) have been identified in the urothelium, a tissue that may be involved in bladder sensory mechanisms. This study investigates the expression and function of mAChRs using cultured urothelial cells from the rat. RT-PCR established the expression of all five mAChR subtypes. Muscarinic agonists acetylcholine (ACh; 10 μM), muscarine (Musc; 20 μM), and oxotremorine methiodide (OxoM; 0.001–20 μM) elicited transient repeatable increases in the intracellular calcium concentration ([Ca2+]i) in ∼50% of cells. These effects were blocked by the mAChR antagonist atropine methyl nitrate (10 μM). The sources of [Ca2+]i changes included influx from external milieu in 63% of cells and influx from external milieu plus release from internal stores in 27% of cells. The use of specific agonists and antagonists (10 μM M1 agonist McN-A-343; 10 μM M2, M3 antagonists AF-DX 116, 4-DAMP) revealed that M1, M2, M3 subtypes were involved in [Ca2+]i changes. The PLC inhibitor U-73122 (10 μM) abolished OxoM-elicited Ca2+ responses in the presence of the M2 antagonist AF-DX 116, suggesting that M1, M3, or M5 mediates [Ca2+]i increases via PLC pathway. ACh (0.1 μM), Musc (10 μM), oxotremorine sesquifumarate (20 μM), and McN-A-343 (1 μM) acting on M1, M2, and M3 mAChR subtypes stimulated ATP release from cultured urothelial cells. In summary, cultured urothelial cells express functional M1, M2, and M3 mAChR subtypes whose activation results in ATP release, possibly through mechanisms involving [Ca2+]i changes.
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Yang, Qing, Andrew D. Sumner, Henry L. Puhl, and Victor Ruiz-Velasco. "M1 and M2 Muscarinic Acetylcholine Receptor Subtypes Mediate Ca2+ Channel Current Inhibition in Rat Sympathetic Stellate Ganglion Neurons." Journal of Neurophysiology 96, no. 5 (November 2006): 2479–87. http://dx.doi.org/10.1152/jn.00093.2006.
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Muscarinic acetylcholine receptors (mAChRs) are known to mediate the acetylcholine inhibition of Ca2+ channels in central and peripheral neurons. Stellate ganglion (SG) neurons provide the main sympathetic input to the heart and contribute to the regulation of heart rate and myocardial contractility. Little information is available regarding mAChR regulation of Ca2+ channels in SG neurons. The purpose of this study was to identify the mAChR subtypes that modulate Ca2+ channel currents in rat SG neurons innervating heart muscle. Accordingly, the modulation of Ca2+ channel currents by the muscarinic cholinergic agonist, oxotremorine-methiodide (Oxo-M), and mAChR blockers was examined. Oxo-M–mediated mAChR stimulation led to inhibition of Ca2+ currents through voltage-dependent (VD) and voltage-independent (VI) pathways. Pre-exposure of SG neurons to the M1 receptor blocker, M1-toxin, resulted in VD inhibition of Ca2+ currents after Oxo-M application. On the other hand, VI modulation of Ca2+ currents was observed after pretreatment of cells with methoctramine (M2 mAChR blocker). The Oxo-M–mediated inhibition was nearly eliminated in the presence of both M1 and M2 mAChR blockers but was unaltered when SG neurons were exposed to the M4 mAChR toxin, M4-toxin. Finally, the results from single-cell RT-PCR and immunofluorescence assays indicated that M1 and M2 receptors are expressed and located on the surface of SG neurons. Overall, the results indicate that SG neurons that innervate cardiac muscle express M1 and M2 mAChR, and activation of these receptors leads to inhibition of Ca2+ channel currents through VI and VD pathways, respectively.
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Mikurova, A. V., V. S. Skvortsov, and O. A. Raevsky. "Computational Evaluation of Selectivity of Inhibition of Muscarinic Receptors M1-M4." Biomedical Chemistry: Research and Methods 1, no. 3 (2018): e00072. http://dx.doi.org/10.18097/bmcrm00072.
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A set of models for preliminary estimation of the inhibition constant values of potential ligands for the 4 acetylcholine muscarinic receptors M1-M4 was developed. The study uses an information about three-dimensional structure of human M1, M2 and M4 receptors, as well as the M3 receptor model, constructed by homology based on the structure of the rat M3 receptor. The Ki values for 42 compounds were obtained from the sources. Modeling of “protein-ligand” complexes was performed using molecular docking and molecular dynamics procedures. The component energy characteristics of the complexes were calculated from data obtained from simulation of molecular dynamics by the MM-PBSA/MM-GBSA methods. These characteristics were used as independent variables to construct the linear regression equations for pKi value predicting. The equations obtained for each receptors allow us to predict pKi with an average accuracy of 0.65 logarithmic units.
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Van Amelsvoort, T. "Muscarinic mechanisms in psychosis: A multimodal imaging study." European Psychiatry 41, S1 (April 2017): s844. http://dx.doi.org/10.1016/j.eurpsy.2017.01.1668.
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BackgroundThe majority of people with psychosis suffer from cognitive problems. These cognitive problems are among the most disabling features of the illness and have a negative effect on clinical outcome. Research has demonstrated that acetylcholine including muscarinic receptors play an important role in cognitive function. A post-mortem study in chronic patients with schizophrenia demonstrated a decrease of 75% of muscarinic M1 receptors.AimThe aim of this study was to investigate the role of M1 receptors in-vivo in brain and cognitive function in psychosis.MethodsThirty medication free patients with psychosis and 30 healthy controls matched for age, gender and IQ were included for 1) 1x IDEX Spect scan to determine M1 binding potential; 2) 2x fMRI scan using a visual memory task; 3) 2x MRS to determine choline concentrations; 2x CANTAB cognitive battery. Except for SPECT all subjects were tested twice, once with placebo and once with biperiden M1 antagonist.ResultatenPatients demonstrated a significant negative correlation between M1 binding potential and cognitive impairments and negative symptom scores on PANSS. Following biperiden challenge, performance on verbal learning and memory was worse. Hippocampal activity was larger during a visual memory task in patients.ConclusieThese results support a role for the M1 receptor in cognitive function in psychosis.Disclosure of interestThe author has not supplied his/her declaration of competing interest.
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Smith, Emery, Peter Chase, Colleen M. Niswender, Thomas J. Utley, Douglas J. Sheffler, Meredith J. Noetzel, Atin Lamsal, et al. "Application of Parallel Multiparametric Cell-Based FLIPR Detection Assays for the Identification of Modulators of the Muscarinic Acetylcholine Receptor 4 (M4)." Journal of Biomolecular Screening 20, no. 7 (April 15, 2015): 858–68. http://dx.doi.org/10.1177/1087057115581770.
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Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer’s disease and other disorders involving impaired cognitive function. In an attempt to identify orthosteric and allosteric modulators of the muscarinic acetylcholine receptor M4 (M4), we developed a homogenous, multiparametric, 1536-well assay to measure M4 receptor agonism, positive allosteric modulation (PAM), and antagonism in a single well. This assay yielded a Z′ of 0.85 ± 0.05 in the agonist, 0.72 ± 0.07 in PAM, and 0.80 ± 0.06 in the antagonist mode. Parallel screening of the M1 and M5 subtypes using the same multiparametric assay format revealed chemotypes that demonstrate selectivity and/or promiscuity between assays and modalities. This identified 503 M4 selective primary agonists, 1450 PAMs, and 2389 antagonist hits. Concentration-response analysis identified 25 selective agonists, 4 PAMs, and 41 antagonists. This demonstrates the advantages of this approach to rapidly identify selective receptor modulators while efficiently removing assay artifacts and undesirable compounds.
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Hulme, E. C., Z. L. Lu, J. W. Saldanha, and M. S. Bee. "Structure and activation of muscarinic acetylcholine receptors." Biochemical Society Transactions 31, no. 1 (February 1, 2003): 29–34. http://dx.doi.org/10.1042/bst0310029.
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A homology model of the M1 muscarinic acetylcholine receptor, based on the X-ray structure of bovine rhodopsin, has been used to interpret the results of scanning and point mutagenesis studies on the receptor's transmembrane (TM) domain. Potential intramolecular interactions that are important for the stability of the protein fold have been identified. The residues contributing to the binding site for the antagonist, N-methyl scopolamine, and the agonist, acetylcholine, have been mapped. The positively charged headgroups of these ligands probably bind in a charge-stabilized aromatic cage formed by amino acid side chains in TM helices TM3, TM6 and TM7, while residues in TM4 may participate as part of a peripheral docking site. Closure of the cage around the headgroup of acetylcholine may be part of the mechanism for transducing binding energy into receptor activation, probably by disrupting a set of Van der Waals interactions between residues lying beneath the binding site that help to constrain the receptor to the inactive state, in the absence of agonist. This may trigger the reorganization of a hydrogen-bonding network between highly conserved residues in the core of the receptor, whose integrity is crucial for achievement of the activated state.
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Filogonio, Renato, Marina R. Sartori, Susie Morgensen, Driele Tavares, Rafael Campos, Augusto S. Abe, Edwin W. Taylor, et al. "Cholinergic regulation along the pulmonary arterial tree of the South American rattlesnake: vascular reactivity, muscarinic receptors, and vagal innervation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 319, no. 2 (August 1, 2020): R156—R170. http://dx.doi.org/10.1152/ajpregu.00310.2019.
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Vascular tone in the reptilian pulmonary vasculature is primarily under cholinergic, muscarinic control exerted via the vagus nerve. This control has been ascribed to a sphincter located at the arterial outflow, but we speculated whether the vascular control in the pulmonary artery is more widespread, such that responses to acetylcholine and electrical stimulation, as well as the expression of muscarinic receptors, are prevalent along its length. Working on the South American rattlesnake ( Crotalus durissus), we studied four different portions of the pulmonary artery (truncus, proximal, distal, and branches). Acetylcholine elicited robust vasoconstriction in the proximal, distal, and branch portions, but the truncus vasodilated. Electrical field stimulation (EFS) caused contractions in all segments, an effect partially blocked by atropine. We identified all five subtypes of muscarinic receptors (M1–M5). The expression of the M1 receptor was largest in the distal end and branches of the pulmonary artery, whereas expression of the muscarinic M3 receptor was markedly larger in the truncus of the pulmonary artery. Application of the neural tracer 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindo-carbocyanine perchlorate (DiI) revealed widespread innervation along the whole pulmonary artery, and retrograde transport of the same tracer indicated two separate locations in the brainstem providing vagal innervation of the pulmonary artery, the medial dorsal motor nucleus of the vagus and a ventro-lateral location, possibly constituting a nucleus ambiguus. These results revealed parasympathetic innervation of a large portion of the pulmonary artery, which is responsible for regulation of vascular conductance in C. durissus, and implied its integration with cardiorespiratory control.
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Pavlov, Valentin, Mahendar Ochani, Meghan Dancho, Yousef Al-Abed, Neil Nathanson, and Kevin Tracey. "Positive allosteric modulation of M1 muscarinic acetylcholine receptors suppresses lethal peripheral inflammation (P5082)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 180.24. http://dx.doi.org/10.4049/jimmunol.190.supp.180.24.
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Abstract Peripheral inflammation can be regulated by activation of brain muscarinic acetylcholine receptor (mAChR)-dependent signaling functionally associated with a vagus-nerve mediated anti-inflammatory circuit (Proc Natl Acad Sci USA, 2006, 5219; Brain Behav Immun, 2009, 23:41). Here, we studied the specific role of the M1 mAChR subtype in this regulation by utilizing BQCA, a highly specific allosteric M1 mAChR activator that crosses the blood-brain barrier. Single drug (5,10 or 20 mg/kg, i.p) administration in mice 1h prior to endotoxin (8 mg/kg, i.p.) dose-dependently reduced serum and splenic TNF levels and significantly improved survival in mice as compared to vehicle-treated controls. Pharmacological blockade of brain mAChRs significantly abolished BQCA anti-inflammatory effects. Furthermore, BQCA (20 mg/kg, i.p.) significantly reduced serum and splenic TNF levels in wild type mice, but failed to alter TNF levels in M1 KO mice. Together these results indicate the anti-inflammatory role of increased functional activity of endogenous acetylcholine on the M1 mAChR by selective allosteric receptor activation. Our findings are of interest for further development of BQCA and other centrally-acting allosteric activators of the M1 mAChR as a novel class of experimental anti-inflammatory therapeutics.
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Lucas, Julie L., Wolfgang Sadee, and Joseph A. DeYoung. "Single nucleotide polymorphisms of the human M1 muscarinic acetylcholine receptor gene." AAPS PharmSci 3, no. 4 (December 2001): 57–61. http://dx.doi.org/10.1208/ps030431.
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