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1
Jaremko, William J., Zhen Huang, Wei Wen, Andrew Wu, Nicholas Karl y Li Niu. "Identification and characterization of RNA aptamers: A long aptamer blocks the AMPA receptor and a short aptamer blocks both AMPA and kainate receptors". Journal of Biological Chemistry 292, n.º 18 (21 de marzo de 2017): 7338–47. http://dx.doi.org/10.1074/jbc.m116.774752.
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AMPA and kainate receptors, along with NMDA receptors, represent different subtypes of glutamate ion channels. AMPA and kainate receptors share a high degree of sequence and structural similarities, and excessive activity of these receptors has been implicated in neurological diseases such as epilepsy. Therefore, blocking detrimental activity of both receptor types could be therapeutically beneficial. Here, we report the use of an in vitro evolution approach involving systematic evolution of ligands by exponential enrichment with a single AMPA receptor target (i.e. GluA1/2R) to isolate RNA aptamers that can potentially inhibit both AMPA and kainate receptors. A full-length or 101-nucleotide (nt) aptamer selectively inhibited GluA1/2R with a KI of ∼5 μm, along with GluA1 and GluA2 AMPA receptor subunits. Of note, its shorter version (55 nt) inhibited both AMPA and kainate receptors. In particular, this shorter aptamer blocked equally potently the activity of both the GluK1 and GluK2 kainate receptors. Using homologous binding and whole-cell recording assays, we found that an RNA aptamer most likely binds to the receptor's regulatory site and inhibits it noncompetitively. Our results suggest the potential of using a single receptor target to develop RNA aptamers with dual activity for effectively blocking both AMPA and kainate receptors.
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Steverding, Dietmar. "Cycle Numbers of Cell Surface Recycling Receptors". Receptors 2, n.º 2 (6 de junio de 2023): 160–65. http://dx.doi.org/10.3390/receptors2020010.
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The cycle number (nc) of a recycling receptor is defined as the average number of round trips (cell surface–endosome–cell surface) the receptor can make before it is degraded. This characteristic parameter of recycling receptors can be easily determined from the receptor’s half-life (t½, the time in which 50% of the receptor is degraded) and cycling time (Tc, the time a receptor needs to complete a round trip). Relationship analyses revealed that nc increases linearly with increasing t½ and decreases exponentially with increasing Tc. For commonly observed t½ and Tc values, it was calculated that recycling receptors have nc values of <300. In addition, it was found that recycling receptors in cancer cells have generally smaller nc values (<100), whereas recycling receptors in normal cells have larger nc values (>100). Based on this latter finding, the cycle number nc may be a useful criterion for distinguishing between cancer and normal cells.
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Santiago, Luis y Ravinder Abrol. "Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods". International Journal of Molecular Sciences 20, n.º 21 (24 de octubre de 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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Wicher, Dieter y Fabio Miazzi. "Functional properties of insect olfactory receptors: ionotropic receptors and odorant receptors". Cell and Tissue Research 383, n.º 1 (enero de 2021): 7–19. http://dx.doi.org/10.1007/s00441-020-03363-x.
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AbstractThe majority of insect olfactory receptors belong to two distinct protein families, the ionotropic receptors (IRs), which are related to the ionotropic glutamate receptor family, and the odorant receptors (ORs), which evolved from the gustatory receptor family. Both receptor types assemble to heteromeric ligand-gated cation channels composed of odor-specific receptor proteins and co-receptor proteins. We here present in short the current view on evolution, function, and regulation of IRs and ORs. Special attention is given on how their functional properties can meet the environmental and ecological challenges an insect has to face.
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Melkes, Barbora, Vendula Markova, Lucie Hejnova y Jiri Novotny. "β-Arrestin 2 and ERK1/2 Are Important Mediators Engaged in Close Cooperation between TRPV1 and µ-Opioid Receptors in the Plasma Membrane". International Journal of Molecular Sciences 21, n.º 13 (29 de junio de 2020): 4626. http://dx.doi.org/10.3390/ijms21134626.
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The interactions between TRPV1 and µ-opioid receptors (MOR) have recently attracted much attention because these two receptors play important roles in pain pathways and can apparently modulate each other’s functioning. However, the knowledge about signaling interactions and crosstalk between these two receptors is still limited. In this study, we investigated the mutual interactions between MOR and TRPV1 shortly after their activation in HEK293 cells expressing these two receptors. After activation of one receptor we observed significant changes in the other receptor’s lateral mobility and vice versa. However, the changes in receptor movement within the plasma membrane were not connected with activation of the other receptor. We also observed that plasma membrane β-arrestin 2 levels were altered after treatment with agonists of both these receptors. Knockdown of β-arrestin 2 blocked all changes in the lateral mobility of both receptors. Furthermore, we found that β-arrestin 2 can play an important role in modulating the effectiveness of ERK1/2 phosphorylation after activation of MOR in the presence of TRPV1. These data suggest that β-arrestin 2 and ERK1/2 are important mediators between these two receptors and their signaling pathways. Collectively, MOR and TRPV1 can mutually affect each other’s behavior and β-arrestin 2 apparently plays a key role in the bidirectional crosstalk between these two receptors in the plasma membrane.
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Roddey, J. C. y G. A. Jacobs. "Information theoretic analysis of dynamical encoding by filiform mechanoreceptors in the cricket cercal system". Journal of Neurophysiology 75, n.º 4 (1 de abril de 1996): 1365–76. http://dx.doi.org/10.1152/jn.1996.75.4.1365.
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1. The stimulus/response properties of 20 mechanosensory receptors in the cricket cercal sensory system were studied using electrophysiological techniques. These receptors innervated filiform hairs of various lengths and directional selectivities. Previous studies have characterized the sensitivity of such cells to the direction of air currents and to the amplitude of sinusoidal stimuli. In the experiments reported here, the quantity and quality of information encoded in the receptors' elicited responses about the dynamics of more complex air current waveforms were characterized. 2. Based on a white analysis of receptor response properties, the median frequency of each receptor's frequency tuning curve was found to be strongly correlated with the length of its associated mechanosensory hair. The receptors connected to hairs > 900 microns encoded frequencies below approximately 150 Hz very accurately and the receptors connected to shorter hairs encoded progressively higher bands of frequencies. These results were interpreted within the constraints imposed by the biomechanics of the air current-to-cercus boundary. 3. The encoding accuracy was expressed in the information theoretic units of bits/second, which characterizes the information transmission rate of a receptor. The information rates of the neuronal spike trains ranged from 75 to 220 bits/s. The information transmission rate was not correlated with the length of the mechanosensory hair. The average amount of information transmitted per action potential was negatively correlated with receptor hair length and ranged between 0.6 and 3.1 bits/spike. Decoding of the receptor responses was restricted to linear transformations of the spike trains. 4. The stimulus/response latencies of the different receptors ranged between 5 and 11 ms, and the integration time of the receptors ranged between 8 and 30 ms. The latency of a receptor was only weakly correlated with the length of its associated hair, and a receptor's integration time was correlated with hair length. 5. The stimulus/response phase difference for receptor cells that innervated hairs longer than approximately 800 microns increased with frequency > 50 Hz. The phase responses for receptor cells connected to hairs < 800 microns did not vary for frequencies > 50 Hz.
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Xie, Peng, Junjie Zhang, Baiyu Chen, Xinwei Li, Wenbo Zhang, Mengdan Zhu, Wei Li, Jianqi Li y Wei Fu. "Computational Methods for Understanding the Selectivity and Signal Transduction Mechanism of Aminomethyl Tetrahydronaphthalene to Opioid Receptors". Molecules 27, n.º 7 (28 de marzo de 2022): 2173. http://dx.doi.org/10.3390/molecules27072173.
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Opioid receptors are members of the group of G protein-couple receptors, which have been proven to be effective targets for treating severe pain. The interactions between the opioid receptors and corresponding ligands and the receptor’s activation by different agonists have been among the most important fields in opioid research. In this study, with compound M1, an active metabolite of tramadol, as the clue compound, several aminomethyl tetrahydronaphthalenes were designed, synthesized and assayed upon opioid receptors. With the resultant compounds FW-AII-OH-1 (Ki = 141.2 nM for the κ opioid receptor), FW-AII-OH-2 (Ki = 4.64 nM for the δ opioid receptor), FW-DI-OH-2 (Ki = 8.65 nM for the δ opioid receptor) and FW-DIII-OH-2 (Ki = 228.45 nM for the δ opioid receptor) as probe molecules, the structural determinants responsible for the subtype selectivity and activation mechanisms were further investigated by molecular modeling and molecular dynamics simulations. It was shown that Y7.43 was a key residue in determining the selectivity of the three opioid receptors, and W6.58 was essential for the selectivity of the δ opioid receptor. A detailed stepwise discovered agonist-induced signal transduction mechanism of three opioid receptors by aminomethyl tetrahydronaphthalene compounds was proposed: the 3–7 lock between TM3 and TM7, the DRG lock between TM3 and TM6 and rearrangement of I3.40, P5.50 and F6.44, which resulted in the cooperative movement in 7 TMs. Then, the structural relaxation left room for the binding of the G protein at the intracellular site, and finally the opioid receptors were activated.
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Wajant, Harald. "Death receptors". Essays in Biochemistry 39 (1 de octubre de 2003): 53–71. http://dx.doi.org/10.1042/bse0390053.
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Death receptors [Fas/Apo-1/CD95, TNF-R1 [tumour necrosis factor (TNF) receptor 1], DR3 [death receptor 3], TRAIL-R1 [TNF-related apoptosis-inducing ligand receptor 1], TRAIL-R2, DR6, p75-NGFR [p75-nerve growth factor receptor], EDAR [ectodermal dysplasia receptor]] form a subgroup of the TNF-R superfamily that can induce apoptosis (programmed cell death) via a conserved cytoplasmic signalling module termed the death domain. Although death receptors have been recognized mainly as apoptosis inducers, there is growing evidence that these receptors also fulfil a variety of nonapoptotic functions. This review is focused on the molecular mechanisms of apoptotic and non-apoptotic death receptor signalling in light of the phenotype of mice deficient in the various death receptors.
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Rossokhin, Alexey V. y Irina N. Sharonova. "Structural pharmacology of GABAА receptors". Annals of Clinical and Experimental Neurology 15, n.º 4 (23 de diciembre de 2021): 44–53. http://dx.doi.org/10.54101/acen.2021.4.5.
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Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian central nervous system (CNS), activating the inotropic type A receptors (GABAА receptors) to provide fast inhibition. GABAА receptors are the main target for various groups of drugs that are widely used in the treatment of CNS disorders.
This review examines the relationship between the physiological effects of GABAА receptor activation and modulation by various substances (including medicinal compounds), the receptor's structure, and the interaction of these substances with specific modulatory sites. Recent advances in cryogenic electron microscopy have led to fundamental improvements in understanding the detailed organization and function of GABAА receptors. This review is based on both the latest structural data obtained from cryogenic electron microscopy and the results of biochemistry and electrophysiology studies, as well as molecular modelling.
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Christopoulos, A., L. T. May, V. A. Avlani y P. M. Sexton. "G-protein-coupled receptor allosterism: the promise and the problem(s)". Biochemical Society Transactions 32, n.º 5 (26 de octubre de 2004): 873–77. http://dx.doi.org/10.1042/bst0320873.
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Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more ‘physiological’ regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validation of allosteric ligands.
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Wank, S. A. "Cholecystokinin receptors". American Journal of Physiology-Gastrointestinal and Liver Physiology 269, n.º 5 (1 de noviembre de 1995): G628—G646. http://dx.doi.org/10.1152/ajpgi.1995.269.5.g628.
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The cholecystokinin (CCK) and gastrin families of peptides act as hormones and neuropeptides on central and peripheral CCK receptors to mediate secretion and motility in the gastrointestinal (GI) tract in the physiological response to a normal meal. CCK and its receptors are also widely distributed in the central nervous system (CNS) and contribute to the regulation of satiety, anxiety, analgesia, and dopamine-mediated behavior. Although the wide distribution, myriad number of functions, and reported pharmacological heterogeneity of CCK receptors would suggest a large number of receptor subtypes, the application of modern molecular biological techniques has identified two CCK receptors, CCK-A receptor (CCK-AR) and CCK-B receptor (CCK-BR), that mediate the actions of CCK and gastrin; gastrin receptors have been found to be identical to CCK-BR. CCK-AR, found predominantly in the GI system and select areas of the CNS, have high affinity for CCK and the nonpeptide antagonist L-364,718, whereas CCK-BR, found predominantly in the CNS and select areas of the GI system, have high affinity for CCK and gastrin and the nonpeptide antagonist L-365,260. Both CCK-AR and CCK-BR are highly conserved between species, although there is some tissue-specific variation in expression. Recombinant receptor expression faithfully reproduces the native receptor pharmacology and signal transduction pathways, allowing direct comparisons of receptor function between species as well as serving as a convenient source of receptor. Our present knowledge of the chromosomal localization, receptor gene structure, and primary sequence will allow further studies in disease association, receptor regulation, and structure-function analysis.
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Trebesova, Hanna, Guendalina Olivero, Mario Marchi y Massimo Grilli. "The Anti-Aggregative Peptide KLVFF Mimics Aβ1-40 in the Modulation of Nicotinic Receptors: Implications for Peptide-Based Therapy". Biomedicines 10, n.º 9 (8 de septiembre de 2022): 2231. http://dx.doi.org/10.3390/biomedicines10092231.
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In recent years, the inhibition of beta-amyloid (Aβ) aggregation has emerged as a potential strategy for Alzheimer’s disease. KLVFF, a small peptide corresponding to the aminoacidic sequence 16-20 of Aβ, reduces Aβ fibrillation dose dependently. Therefore, the toxic and functional characterization of its brain activity is fundamental for clarifying its potential therapeutic role. Accordingly, we studied the modulatory role of KLVFF on the cholinergic receptors regulating dopamine and noradrenaline release in rat synaptosomes. Nicotinic receptors on dopaminergic nerve terminals in the nucleus acccumbens are inhibited by KLVFF, which closely resembles full-length Aβ1-40. Moreover, KLVFF entrapped in synaptosomes does not modify the nicotinic receptor’s function, suggesting that external binding to the receptor is required for its activity. The cholinergic agent desformylflustrabromine counteracts the KLVFF effect. Remarkably, muscarinic receptors on dopaminergic terminals and nicotinic receptors regulating noradrenaline release in the hippocampus are completely insensitive to KLVFF. Based on our findings, KLVFF mimics Aβ1-40 as a negative modulator of specific nicotinic receptor subtypes affecting dopamine transmission in the rat brain. Therefore, new pharmacological strategies using the anti-aggregative properties of KLVFF need to be evaluated for potential interference with nicotinic receptor-mediated transmission.
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Okusa, Mark D., Liping Huang, Akemi Momose-Hotokezaka, Long P. Huynh y Amy J. Mangrum. "Regulation of adenylyl cyclase in polarized renal epithelial cells by G protein-coupled receptors". American Journal of Physiology-Renal Physiology 273, n.º 6 (1 de diciembre de 1997): F883—F891. http://dx.doi.org/10.1152/ajprenal.1997.273.6.f883.
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We employed two guanine nucleotide binding protein (G protein)-coupled receptors known to be targeted to opposite domains in renal epithelial cells to test the hypothesis that the polarized receptor expression of receptors regulates the activity of the receptor’s effector molecule, adenylyl cyclase. We used LLC-PK1 cells stably transfected with cDNA encoding the α2B-adrenergic receptor (α2B-AR) or A1-adenosine receptor (A1-AdR). Immunohistochemistry and Western blot analysis confirmed the basolateral and apical expression of α2B-ARs and A1-AdRs, respectively. Adenylyl cyclase activity was assessed by measuring cAMP accumulation following the addition of forskolin (10 μM) in the presence of 3-isobutyl-1-methylxanthine to apical or basolateral chambers of confluent monolayers. A five- to sixfold increase in cAMP accumulation occurred following apical (or basolateral) stimulation of LLC-PK1 cells expressing apical (or basolateral) receptors in comparison to forskolin stimulation of corresponding domains of untransfected cells. We conclude 1) adenylyl cyclase activity is present at or near the apical and basolateral domains of LLC-PK1 cells, and 2) factors that regulate the polarized expression of inhibitory G protein-coupled receptors may also regulate local adenylyl cyclase activity.
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Gado, Francesca, Serena Meini, Simone Bertini, Maria Digiacomo, Marco Macchia y Clementina Manera. "Allosteric modulators targeting cannabinoid cb1 and cb2 receptors: implications for drug discovery". Future Medicinal Chemistry 11, n.º 15 (agosto de 2019): 2019–37. http://dx.doi.org/10.4155/fmc-2019-0005.
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Allosteric modulators of cannabinoid receptors hold great therapeutic potential, as they do not possess intrinsic efficacy, but instead enhance or diminish the receptor's response of orthosteric ligands allowing for the tempering of cannabinoid receptor signaling without the desensitization, tolerance and dependence. Allosteric modulators of cannabinoid receptors have numerous advantages over the orthosteric ligands such as higher receptor type selectivity, probe dependence and biased signaling, so they have a great potential to separate the therapeutic benefits from side effects own of orthosteric ligands. This review aims to give an overview of the CB1 and CB2 receptor allosteric modulators highlighting the structure–activity relationship and pharmacological profile of each classes, and their future promise.
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Doukhanina, Elena V., Nestor R. Apuya, Hye-Dong Yoo, Chuan-Yin Wu, Patricia Davidow, Shannon Krueger, Richard B. Flavell, Richard Hamilton y Steven C. Bobzin. "Expression of Human Nuclear Receptors in Plants for the Discovery of Plant-Derived Ligands". Journal of Biomolecular Screening 12, n.º 3 (26 de enero de 2007): 385–95. http://dx.doi.org/10.1177/1087057107299255.
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Plants have the potential to produce a wide array of secondary metabolites that have utility as drugs to treat human diseases. To tap this potential, functional human nuclear receptors have been expressed in plants to create in planta screening assays as a tool to discover natural product ligands. Assays have been designed and validated using 3 nuclear receptors: the estrogen receptor (ER), the androgen receptor (AR), and the heterodimeric retinoid X receptor-α plus thyroid hormone receptorβ (RXRA/THRB). Nuclear receptor—reporter constructs have been expressed in plants to detect the presence of natural ligands that are produced de novo in several plant species during different stages of development, in various tissues, and in response to different stress elicitors. Screening experiments with ER, AR, and RXRA/THRB have been conducted, leading to the identification of plant sources of natural product ligands of human nuclear receptors. This in planta screen has led to the identification of previously unreported ER ligands, providing evidence of the complementary value of this approach to current in vitro high-throughput screening assays. ( Journal of Biomolecular Screening 2007:385-395)
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Jose, P. A., J. R. Raymond, M. D. Bates, A. Aperia, R. A. Felder y R. M. Carey. "The renal dopamine receptors." Journal of the American Society of Nephrology 2, n.º 8 (febrero de 1992): 1265–78. http://dx.doi.org/10.1681/asn.v281265.
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Dopamine is an endogenous catecholamine that modulates many functions including behavior, movement, nerve conduction, hormone synthesis and release, blood pressure, and ion fluxes. Dopamine receptors in the brain have been classically divided into D1 and D2 subtypes, based on pharmacological data. However, molecular biology techniques have identified many more dopamine receptor subtypes. Several of the receptors cloned from the brain correspond to the classically described D1 and D2 receptors. Several D1 receptor subtypes have been cloned (D1A, D1B, and D5) and are each coupled to the stimulation of adenylyl cyclase. The D2 receptor has two isoforms, a shorter form, composed of 415 amino acids, is termed the D2short receptor. The long form, called the D2long receptor, is composed of 444 amino acids; both are coupled to the inhibition of adenylyl cyclase. The D3 and D4 receptors are closely related to, but clearly distinct from, the D2 receptor. They have not yet been linked to adenylyl cyclase activity. Outside of the central nervous system, the peripheral dopamine receptors have been classified into the DA1 and DA2 subtypes, on the basis of synaptic localization. The pharmacological properties of DA1 receptors roughly approximate those of D1 and D5 receptors, whereas those of DA2 receptors approximate those of D2 receptors. A renal dopamine receptor with some pharmacological features of the D2 receptor but not linked to adenylyl cyclase has been described in the renal cortex and inner medulla. In the inner medulla, this D2-like receptor, termed DA2k, is linked to stimulation of prostaglandin E2 production, apparently due to stimulation of phospholipase A2. Of the cloned dopamine receptors, only the mRNA of the D3 receptor has been reported in the kidney. The DA1 receptor in the kidney is associated with renal vasodilation and an increase in electrolyte excretion. The DA1-related vasodilation and inhibition of electrolyte transport is mediated by cAMP. The role of renal DA2 receptors remains to be clarified. Although DA1 and DA2 receptors may act in concert to decrease transport in the renal proximal convoluted tubule, the overall function of DA2 receptors may be actually the opposite of those noted for DA1 receptors. Dopamine has been postulated to act as an intrarenal natriuretic hormone. Moreover, an aberrant renal dopaminergic system may play a role in the pathogenesis of some forms of hypertension. A decreased renal production of dopamine and/or a defective transduction of the dopamine signal is/are present in some animal models of experimental hypertension as well as in some forms of human essential hypertension.
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Johnson, L. S., K. W. Dunn, B. Pytowski y T. E. McGraw. "Endosome acidification and receptor trafficking: bafilomycin A1 slows receptor externalization by a mechanism involving the receptor's internalization motif." Molecular Biology of the Cell 4, n.º 12 (diciembre de 1993): 1251–66. http://dx.doi.org/10.1091/mbc.4.12.1251.
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To examine the relationship between endosome acidification and receptor trafficking, transferrin receptor trafficking was characterized in Chinese hamster ovary cells in which endosome acidification was blocked by treatment with the specific inhibitor of the vacuolar H(+)-ATPase, bafilomycin A1. Elevating endosome pH slowed the receptor externalization rate to approximately one-half of control but did not affect receptor internalization kinetics. The slowed receptor externalization required the receptor's cytoplasmic domain and was largely eliminated by substitutions replacing either of two aromatic amino acids within the receptor's cytoplasmic YTRF internalization motif. These results confirm, using a specific inhibitor of the vacuolar proton pump, that proper endosome acidification is necessary to maintain rapid recycling of intracellular receptors back to the plasma membrane. Moreover, receptor return to the plasma membrane is slowed in the absence of proper endosome acidification by a signal-dependent mechanism involving the receptor's cytoplasmic tyrosine-containing internalization motif. These results, in conjunction with results from other studies, suggest that the mechanism for clustering receptors in plasma membrane clathrin-coated pits may be an example of a more general mechanism that determines the dynamic distribution of membrane proteins among various compartments with luminal acidification playing a crucial role in this process.
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Mao, S. Y., J. R. Pfeiffer, J. M. Oliver y H. Metzger. "Effects of subunit mutation on the localization to coated pits and internalization of cross-linked IgE-receptor complexes." Journal of Immunology 151, n.º 5 (1 de septiembre de 1993): 2760–74. http://dx.doi.org/10.4049/jimmunol.151.5.2760.
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Abstract IgE receptors of mast cells, Fc epsilon RI, localize to coated pits and internalize after cross-linking. We investigated whether any one of the receptor's four distinctive cytoplasmic domains regulates these phenomena. COS cells, which lack Fc epsilon RI entirely, and P815 mouse mastocytoma cells that lack the alpha and beta subunits of the tetrameric Fc epsilon RI (alpha beta gamma 2), were transfected with wild-type, incomplete, or variant Fc epsilon RI. IgE-receptor complexes were observed by electron microscopy. Before cross-linking with anti-IgE gold particles, receptors were not preferentially localized to coated pits, which occupy approximately 1% of the cell surface. After cross-linking, up to 10 to 20% of the wild-type and most other receptor variants were in coated pits in transfected P815 cells at any one time. beta-less variants localized normally but, surprisingly, receptors containing a variant beta subunit showed reduced localization. "Receptors" consisting simply of the lipid-anchored ectodomains of the human alpha subunit failed to localize to coated pits. In general, cross-linked receptors that localized to coated pits were progressively internalized, whereas receptors that failed to accumulate in coated pits were not. We conclude that no single cytoplasmic domain of the Fc epsilon RI uniquely controls its ligand-induced localization to coated pits and internalization.
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Ide, Hiroki y Hiroshi Miyamoto. "Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor". Disease Markers 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/840640.
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There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression.
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Ayyad, Rezk R., Ahmed M. Mansour, Ahmed M. Nejm, Yasser Abdel Allem Hassan y Ahmed R. Ayyad. "The Direct Cholinomimetics and Cholinergic Blocking Agents Depend on Stereo Specificity of Cholinergic Receptors". Current Research in Medical Sciences 3, n.º 2 (junio de 2024): 1–7. http://dx.doi.org/10.56397/crms.2024.06.01.
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The cholinergic receptors are the site of action of acetylcholine (Ach) and acetylcholine like substance and anti-cholinergic agents, these receptors either muscarinic receptors or nicotinic receptors the exactly difference between them the area of receptor, where the muscarinic receptor is short than nicotinic receptor (nearly 4.5 and 6 Angstrom, respectively) and the muscarine act on muscarinic receptors and nicotine act on nicotinic receptors. The direct cholinomimetics and cholinergic blocking agents are characterized by chemical features adjustment with these receptors. This can be explained by the structure activity relationship (SAR) of direct cholinomimetic and cholinergic blocking agent drugs. The important examples of stereo specificity of receptors are hexamethonium and decamethonium, which is binding with the nicotinic receptor by specific mechanism (via width and length respectively of the receptor).
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Liu, Xiangyu, Ali Masoudi, Alem W. Kahsai, Li-Yin Huang, Biswaranjan Pani, Dean P. Staus, Paul J. Shim et al. "Mechanism of β2AR regulation by an intracellular positive allosteric modulator". Science 364, n.º 6447 (27 de junio de 2019): 1283–87. http://dx.doi.org/10.1126/science.aaw8981.
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Drugs targeting the orthosteric, primary binding site of G protein–coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal structure of the prototypic β2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor’s inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β2- over the β1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.
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del Mármol, Josefina, Mackenzie A. Yedlin y Vanessa Ruta. "The structural basis of odorant recognition in insect olfactory receptors". Nature 597, n.º 7874 (4 de agosto de 2021): 126–31. http://dx.doi.org/10.1038/s41586-021-03794-8.
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AbstractOlfactory systems must detect and discriminate amongst an enormous variety of odorants1. To contend with this challenge, diverse species have converged on a common strategy in which odorant identity is encoded through the combinatorial activation of large families of olfactory receptors1–3, thus allowing a finite number of receptors to detect a vast chemical world. Here we offer structural and mechanistic insight into how an individual olfactory receptor can flexibly recognize diverse odorants. We show that the olfactory receptor MhOR5 from the jumping bristletail4Machilis hrabei assembles as a homotetrameric odorant-gated ion channel with broad chemical tuning. Using cryo-electron microscopy, we elucidated the structure of MhOR5 in multiple gating states, alone and in complex with two of its agonists—the odorant eugenol and the insect repellent DEET. Both ligands are recognized through distributed hydrophobic interactions within the same geometrically simple binding pocket located in the transmembrane region of each subunit, suggesting a structural logic for the promiscuous chemical sensitivity of this receptor. Mutation of individual residues lining the binding pocket predictably altered the sensitivity of MhOR5 to eugenol and DEET and broadly reconfigured the receptor’s tuning. Together, our data support a model in which diverse odorants share the same structural determinants for binding, shedding light on the molecular recognition mechanisms that ultimately endow the olfactory system with its immense discriminatory capacity.
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Althumairy, Duaa, Xiaoping Zhang, Nicholas Baez, George Barisas, Deborah A. Roess, George R. Bousfield y Debbie C. Crans. "Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors". Diseases 8, n.º 3 (15 de septiembre de 2020): 35. http://dx.doi.org/10.3390/diseases8030035.
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Signal transduction by luteinizing hormone receptors (LHRs) and follicle-stimulating hormone receptors (FSHRs) is essential for the successful reproduction of human beings. Both receptors and the thyroid-stimulating hormone receptor are members of a subset of G-protein coupled receptors (GPCRs) described as the glycoprotein hormone receptors. Their ligands, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and a structurally related hormone produced in pregnancy, human chorionic gonadotropin (hCG), are large protein hormones that are extensively glycosylated. Although the primary physiologic functions of these receptors are in ovarian function and maintenance of pregnancy in human females and spermatogenesis in males, there are reports of LHRs or FSHRs involvement in disease processes both in the reproductive system and elsewhere. In this review, we evaluate the aggregation state of the structure of actively signaling LHRs or FSHRs, their functions in reproduction as well as summarizing disease processes related to receptor mutations affecting receptor function or expression in reproductive and non-reproductive tissues. We will also present novel strategies for either increasing or reducing the activity of LHRs signaling. Such approaches to modify signaling by glycoprotein receptors may prove advantageous in treating diseases relating to LHRs or FSHRs function in addition to furthering the identification of new strategies for modulating GPCR signaling.
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Sheppard, Karen E. "II. Intestinal corticosteroid receptors". American Journal of Physiology-Gastrointestinal and Liver Physiology 282, n.º 5 (1 de mayo de 2002): G742—G746. http://dx.doi.org/10.1152/ajpgi.00531.2001.
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Two corticosteroid receptors have been cloned; they are the glucocorticoid receptor and the mineralocorticoid receptor. These receptors are members of the steroid/thyroid/retinoid receptor family of nuclear transactivating factors, which are characterized by two highly conserved zinc fingers in the central DNA binding domain, a COOH-terminal domain that encompasses the ligand binding site, and a variable NH2-terminal domain. In addition to these cloned receptors, other corticosteroid receptors have recently been identified in intestine. Steroid binding studies have identified two novel putative corticosteroid receptors in intestinal epithelia, and molecular cloning studies have detected two low-affinity receptors in small intestine that are activated by corticosteroids and induce CYP3A gene expression. This article focuses on the identification of these novel corticosteroid receptors and the potential role they may play in intestinal physiology.
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Cato, A. C. y H. Ponta. "Different regions of the estrogen receptor are required for synergistic action with the glucocorticoid and progesterone receptors". Molecular and Cellular Biology 9, n.º 12 (diciembre de 1989): 5324–30. http://dx.doi.org/10.1128/mcb.9.12.5324-5330.1989.
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Estrogen and progesterone or estrogen and glucocorticoid receptors functionally cooperate in gene activation if their cognate binding sites are close to one another. These interactions have been described as synergism of action of the steroid receptors. The mechanism by which synergism is achieved is not clear, although protein-protein interaction of the receptors is one of the favorite models. In transfection experiments with receptor expression vectors and a reporter gene containing estrogen and progesterone-glucocorticoid receptor binding sites, we have examined the effects that different portions of the various receptors have on synergism. N-terminal domains of the chicken progesterone and human glucocorticoid receptors, when deleted, abolished the synergistic action of these receptors with the estrogen receptor. Deletion of the carboxy-terminal amino acids 341 to 595 of the estrogen receptor produced a mutant receptor that could not trans-activate on its own. This mutant receptor did not affect the action of the glucocorticoid receptor but functioned synergistically with the progesterone receptor. We therefore conclude that the synergistic action of the receptors for estrogen and progesterone is mechanistically different from the synergistic action of the receptors for estrogen and glucocorticoid.
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Cato, A. C. y H. Ponta. "Different regions of the estrogen receptor are required for synergistic action with the glucocorticoid and progesterone receptors." Molecular and Cellular Biology 9, n.º 12 (diciembre de 1989): 5324–30. http://dx.doi.org/10.1128/mcb.9.12.5324.
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Estrogen and progesterone or estrogen and glucocorticoid receptors functionally cooperate in gene activation if their cognate binding sites are close to one another. These interactions have been described as synergism of action of the steroid receptors. The mechanism by which synergism is achieved is not clear, although protein-protein interaction of the receptors is one of the favorite models. In transfection experiments with receptor expression vectors and a reporter gene containing estrogen and progesterone-glucocorticoid receptor binding sites, we have examined the effects that different portions of the various receptors have on synergism. N-terminal domains of the chicken progesterone and human glucocorticoid receptors, when deleted, abolished the synergistic action of these receptors with the estrogen receptor. Deletion of the carboxy-terminal amino acids 341 to 595 of the estrogen receptor produced a mutant receptor that could not trans-activate on its own. This mutant receptor did not affect the action of the glucocorticoid receptor but functioned synergistically with the progesterone receptor. We therefore conclude that the synergistic action of the receptors for estrogen and progesterone is mechanistically different from the synergistic action of the receptors for estrogen and glucocorticoid.
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Ecke, Denise, Theodor Hanck, Mohan E. Tulapurkar, Rainer Schäfer, Matthias Kassack, Rolf Stricker y Georg Reiser. "Hetero-oligomerization of the P2Y11 receptor with the P2Y1 receptor controls the internalization and ligand selectivity of the P2Y11 receptor". Biochemical Journal 409, n.º 1 (11 de diciembre de 2007): 107–16. http://dx.doi.org/10.1042/bj20070671.
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Nucleotides signal through purinergic receptors such as the P2 receptors, which are subdivided into the ionotropic P2X receptors and the metabotropic P2Y receptors. The diversity of functions within the purinergic receptor family is required for the tissue-specificity of nucleotide signalling. In the present study, hetero-oligomerization between two metabotropic P2Y receptor subtypes is established. These receptors, P2Y1 and P2Y11, were found to associate together when co-expressed in HEK293 cells. This association was detected by co-pull-down, immunoprecipitation and FRET (fluorescence resonance energy transfer) experiments. We found a striking functional consequence of the interaction between the P2Y11 receptor and the P2Y1 receptor where this interaction promotes agonist-induced internalization of the P2Y11 receptor. This is remarkable because the P2Y11 receptor by itself is not able to undergo endocytosis. Co-internalization of these receptors was also seen in 1321N1 astrocytoma cells co-expressing both P2Y11 and P2Y1 receptors, upon stimulation with ATP or the P2Y1 receptor-specific agonist 2-MeS-ADP. 1321N1 astrocytoma cells do not express endogenous P2Y receptors. Moreover, in HEK293 cells, the P2Y11 receptor was found to functionally associate with endogenous P2Y1 receptors. Treatment of HEK293 cells with siRNA (small interfering RNA) directed against the P2Y1 receptor diminished the agonist-induced endocytosis of the heterologously expressed GFP–P2Y11 receptor. Pharmacological characteristics of the P2Y11 receptor expressed in HEK293 cells were determined by recording Ca2+ responses after nucleotide stimulation. This analysis revealed a ligand specificity which was different from the agonist profile established in cells expressing the P2Y11 receptor as the only metabotropic nucleotide receptor. Thus the hetero-oligomerization of the P2Y1 and P2Y11 receptors allows novel functions of the P2Y11 receptor in response to extracellular nucleotides.
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Stephenson, F. A. "Structure and trafficking of NMDA and GABAA receptors". Biochemical Society Transactions 34, n.º 5 (1 de octubre de 2006): 877–81. http://dx.doi.org/10.1042/bst0340877.
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The fidelity of synaptic function is dependent on the expression of the appropriate neurotransmitter receptor subtype, the targeting and trafficking of receptors to synapses as well as the regulation of the actual number of receptors at synapses. GABAA (γ-aminobutyric acid type A) receptors and NMDA (N-methyl-D-aspartate) receptors are both examples of ligand-gated, heteromeric neurotransmitter receptors whose cell-surface expression is dynamic and tightly regulated. NMDA receptors are localized at excitatory synapses. These synapses are highly structured but dynamic, with the interplay between NMDA receptors and NMDA receptor-associated scaffolding proteins regulating the expression of functional cell-surface synaptic and extrasynaptic receptors. Based on current information, inhibitory synapses seem to be less ordered, and a GABAA receptor equivalent of PSD-95 (postsynaptic density-95), the scaffolding molecule pivotal to the organization of NMDA receptor complexes at synapses, is yet to be validated. In the present paper, processes regulating the trafficking, assembly and molecular organization of both NMDA receptors and GABAA receptors will be discussed.
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Srejovic, Ivan, Vladimir Jakovljevic, Vladimir Zivkovic y Dragan Djuric. "Possible Role of N-Methyl-D-Aspartate Receptors in Physiology and Pathophysiology of Cardiovascular System". Serbian Journal of Experimental and Clinical Research 20, n.º 1 (1 de marzo de 2019): 3–13. http://dx.doi.org/10.1515/sjecr-2017-0010.
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Abstract N-methyl-D-aspartate (NMDA) receptors belong to ionotropic glutamate receptor family, together with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainite receptors and δ-receptors. All of these receptors are tetramers composed of four subunits. NMDA receptors have several unique features in relation to other ionotropic glutamate receptors: requirement for simultaneous action of two coagonists, glutamate and glycine; dual control of receptor activation, ligand-dependent (by glutamate and glycine) and voltage-dependent (Mg2+ block) control; and influx of considerable amounts of Ca2+ following receptor activation. Increasing number of researches deals with physiological and pathophysiological roles of NMDA receptors outside of nerve tissues, especially in the cardiovascular system. NMDA receptors are found in all cell types represented in cardiovascular system, and their overstimulation in pathological conditions, such as hyperhomocysteinemia, is related to a range of cardiovascular disorders. On the other hand we demonstrated that blockade of NMDA receptors depresses heart function. There is a need for the intensive study of NMDA receptor in cardiovascular system as potential theraputical target both in prevention and treatment of cardiovascular disorders.
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Baker, ME. "Adrenal and sex steroid receptor evolution: environmental implications". Journal of Molecular Endocrinology 26, n.º 2 (1 de abril de 2001): 119–25. http://dx.doi.org/10.1677/jme.0.0260119.
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The nuclear receptor family responds to a diverse group of ligands, including steroids, retinoids, thyroid hormone, prostaglandins and fatty acids. Previous sequence analyses of adrenal and sex steroid receptors indicate that they form a clade separate from other nuclear receptors. However, the relationships of adrenal and sex steroid receptors to each other and to their ancestors are not fully understood. We have used new information from androgen, estrogen, mineralocorticoid and progesterone receptors in fish to better resolve the phylogeny of adrenal and sex steroid receptors. Sequence divergence between fish and mammalian steroid receptors correlates with differences in steroid specificity, suggesting that phylogeny needs to be considered in evaluating the endocrine effects of xenobiotics. Among the vertebrate steroid receptors, the most ancient is the estrogen receptor. The phylogeny indicates that adrenal and sex steroid receptors arose in a jawless fish or a protochordate and that changes in the sequence of the hormone-binding domain have slowed considerably in land vertebrates. The retinoid X receptor clade is closest to the adrenal and sex steroid receptor clade. Retinoid X receptor is noteworthy for its ability to form dimers with other nuclear receptors, an important mechanism for regulating the action of retinoid X receptor and its dimerization partners. In contrast, the adrenal and sex steroid receptors bind to DNA as homodimers. Moreover, unliganded adrenal and sex steroid receptors form complexes with heat shock protein 90. Thus, the evolution of adrenal and sex steroid receptors involved changes in protein-protein interactions as well as ligand recognition.
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Funder, John W. "Mineralocorticoid receptors and glucocorticoid receptors". Clinical Endocrinology 45, n.º 6 (diciembre de 1996): 651–56. http://dx.doi.org/10.1046/j.1365-2265.1996.8540862.x.
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Kunapuli, Satva P. "P2 Receptors and Platelet Activation". Scientific World JOURNAL 2 (2002): 424–33. http://dx.doi.org/10.1100/tsw.2002.106.
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Adenosine diphosphate (ADP) plays a crucial role in hemostasis and thrombosis by activating platelets. In platelets, the classical P2T receptor is now resolved into three P2 receptor subtypes: the P2Y1, the P2Y12, and the P2X1 receptors. Both pharmacological and molecular biological approaches have confirmed the role of the P2Y1 and P2Y12 receptors in the ADP-induced platelet fibrinogen receptor activation. The P2Y1 and the P2X1 receptors independently contribute to platelet shape change. Whereas the P2Y12 receptor mediates the potentiation of dense granule release reaction, both the P2Y1 and P2Y12 receptors play an important role in the ADP-induced phospholipase A2 activation. The signaling events downstream of these receptors leading to the physiological effects remain elusive, and they are yet to be delineated.
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Cottrell, Jeffrey R., Gilles R. Dubé, Christophe Egles y Guosong Liu. "Distribution, Density, and Clustering of Functional Glutamate Receptors Before and After Synaptogenesis in Hippocampal Neurons". Journal of Neurophysiology 84, n.º 3 (1 de septiembre de 2000): 1573–87. http://dx.doi.org/10.1152/jn.2000.84.3.1573.
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Postsynaptic differentiation during glutamatergic synapse formation is poorly understood. Using a novel biophysical approach, we have investigated the distribution and density of functional glutamate receptors and characterized their clustering during synaptogenesis in cultured hippocampal neurons. We found that functional α-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) and N-methyl-d-aspartate (NMDA) receptors are evenly distributed in the dendritic membrane before synaptogenesis with an estimated density of 3 receptors/μm2. Following synaptogenesis, functional AMPA and NMDA receptors are clustered at synapses with a density estimated to be on the order of 104 receptors/μm2, which corresponds to ∼400 receptors/synapse. Meanwhile there is no reduction in the extrasynaptic receptor density, which indicates that the aggregation of the existing pool of receptors is not the primary mechanism of glutamate receptor clustering. Furthermore our data suggest that the ratio of AMPA to NMDA receptor density may be regulated to be close to one in all dendritic locations. We also demonstrate that synaptic AMPA and NMDA receptor clusters form with a similar time course during synaptogenesis and that functional AMPA receptors cluster independently of activity and glutamate receptor activation, including following the deletion of the NMDA receptor NR1 subunit. Thus glutamate receptor activation is not necessary for the insertion, clustering, and activation of functional AMPA receptors during synapse formation, and this process is likely controlled by an activity-independent signal.
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Soos, M. A. y K. Siddle. "Immunological relationships between receptors for insulin and insulin-like growth factor I. Evidence for structural heterogeneity of insulin-like growth factor I receptors involving hybrids with insulin receptors". Biochemical Journal 263, n.º 2 (15 de octubre de 1989): 553–63. http://dx.doi.org/10.1042/bj2630553.
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The receptors for insulin and insulin-like growth factor-I (IGF-I) are closely related in primary sequence and overall structure. We have examined the immunological relationships between these receptors by testing the reactivity of anti-(insulin receptor) monoclonal antibodies with IGF-I receptors in various tissues and cell lines. Antibodies for six distinct epitopes reacted with a subfraction of IGF-I receptors, as shown by inhibition of 125I-IGF-I binding, precipitation of 125I-IGF-I-receptor complexes or immunodepletion of receptor from tissue extracts before binding assays. Both immunoreactive and non-immunoreactive subfractions displayed the expected properties of ‘classical’ IGF-I receptors, in terms of relative affinities for IGF-I and insulin. The proportion of total IGF-I receptors which was immunoreactive varied in different cell types, being approx. 40% in Hep G2 cells, 35-40% in placental membranes and 75-85% in IM-9 cells. The immunoreactive fraction was somewhat higher in solubilized receptors than in the corresponding intact cells or membranes. A previously described monoclonal antibody, alpha-IR-3, specific for IGF-I receptors, inhibited IGF-I binding by more than 80% in all preparations. When solubilized placental receptors were pretreated with dithiothreitol (DTT) under conditions reported to reduce intramolecular (class I) disulphide bonds, the immunoreactivity of IGF-I receptors was abolished although total IGF-I binding was little affected. Under the same conditions insulin receptors remained fully immunoreactive. When solubilized receptor preparations were fractionated by gel filtration, both IGF-I and insulin receptors ran as symmetrical peaks of identical mobility. After DTT treatment, the IGF-I receptor was partially converted to a lower molecular mass form which was not immunoreactive. The insulin receptor peak showed a much less pronounced skewing and remained fully immunoreactive in all fractions. It is concluded that the anti- (insulin receptor) antibodies do not react directly with IGF-I receptor polypeptide, and that the apparent immunoreactivity of a subfraction of IGF-I receptors reflects their physical association with insulin receptors, both in cell extracts and in intact cells. The most likely basis for this association appears to be a ‘hybrid’ receptor containing one half (alpha beta) of insulin receptor polypeptide and the other (alpha‘beta’) of IGF-I receptor polypeptide within the native (alpha beta beta‘alpha’) heterotetrameric structure.
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Khatri, Shailesh N., Wan-Chen Wu, Ying Yang y Jason R. Pugh. "Direction of action of presynaptic GABAA receptors is highly dependent on the level of receptor activation". Journal of Neurophysiology 121, n.º 5 (1 de mayo de 2019): 1896–905. http://dx.doi.org/10.1152/jn.00779.2018.
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Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABAA receptors. However, reports of the functional consequences of presynaptic GABAA receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABAA receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABAA receptors in mice. Activation of GABAA receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABAB receptors reduces GABAA receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABAA receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABAA receptors to enhance or inhibit transmitter release at the same synapse depending on activity level provides a new mechanism for fine control of synaptic transmission by GABA and may explain conflicting reports of presynaptic GABAA receptor function across synapses. NEW & NOTEWORTHY GABAA receptors are widely expressed at presynaptic terminals in the central nervous system. However, previous reports have produced conflicting results on the function of these receptors at different synapses. We show that presynaptic GABAA receptor function is strongly dependent on the level of receptor activation. Low levels of receptor activation enhance transmitter release, whereas higher levels of activation inhibit release at the same synapses. This provides a novel mechanism by which presynaptic GABAA receptors fine-tune synaptic transmission.
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Wetter, Justin A., Chetana Revankar y Bonnie J. Hanson. "Utilization of the TangoTM β-Arrestin Recruitment Technology for Cell-Based EDG Receptor Assay Development and Interrogation". Journal of Biomolecular Screening 14, n.º 9 (2 de septiembre de 2009): 1134–41. http://dx.doi.org/10.1177/1087057109343809.
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Cellular assay development for the endothelial differentiation gene (EDG) family of G-protein-coupled receptors (GPCRs) and related lysophospholipid (LP) receptors is complicated by endogenous receptor expression and divergent receptor signaling. Endogenously expressed LP receptors exist in most tissue culture cell lines. these LP receptors, along with other endogenously expressed GPCRs, contribute to off-target signaling that can complicate interpretation of second-messenger-based cellular assay results. these receptors also activate a diverse and divergent set of cellular signaling pathways, necessitating the use of a variety of assay formats with mismatched procedures and functional readouts. this complicates examination and comparison of these receptors across the entire family. the tango™ technology uses the conserved β-arrestin-dependent receptor deactivation process to allow interrogation of the EDG and related receptors with a single functional assay. this method also isolates the target receptor signal, allowing the use of tissue culture cell lines regardless of their endogenous receptor expression. the authors describe the use of this technique to build cell-based receptor-specific assays for all 8 members of the EDG receptor family as well as the related LPA receptors GPR23, GPR92, and GPR87. In addition, they demonstrate the value of this technology for identification and investigation of functionally selective receptor compounds as demonstrated by the immunosuppressive compound FtY720-P and its action at the EDG1 and EDG3 receptors. ( Journal of Biomolecular Screening 2009:1134-1141)
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Waage, A., N. Liabakk, E. Lien, J. Lamvik y T. Espevik. "p55 and p75 tumor necrosis factor receptors in patients with chronic lymphocytic leukemia". Blood 80, n.º 10 (15 de noviembre de 1992): 2577–83. http://dx.doi.org/10.1182/blood.v80.10.2577.2577.
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Abstract We studied the expression of the two tumor necrosis factor (TNF) receptors, p55 and p75, on B cells from patients with chronic lymphocytic leukemia (CLL), and the presence of soluble TNF receptors in serum. Expression of membrane-associated receptors was quantified by double labeling of peripheral blood mononuclear cells (PBMC) with monoclonal antibodies against CD19 and p55/p75 TNF receptors and flow cytometry. A high fraction of the CD19+ cells expressed the p55 receptor (44% +/- 34% [SD]) and p75 receptor (61% +/- 31%). In healthy controls, 0% to 1% of the CD19+ cells expressed the p55 receptor and 0% to 10% expressed the p75 receptor. Incubation of CD19+ cells with 10 ng/mL of TNF increased the incorporation of thymidine in 11 patients tested, and this was decreased to 65% (P < .05) by antibodies to the p55 receptor or the p75 receptor, and to 35% +/- 7% (P < .001) when both antibodies were combined. With an enzyme-linked immunoassay, we measured soluble TNF receptors in serum from CLL patients. The mean level of p55 receptors was increased to 12.9 +/- 8.9 ng/mL (P < .000001 v normal). The mean level of p75 receptors was increased to 13 +/- 24 ng/mL (P = .01 v normal). The membrane expression of the two receptors was positively correlated (r +/- 97, P < .01); however, there was no correlation between membrane expression and serum concentration of either receptor. Autologous serum containing high levels of soluble TNF receptors inhibited TNF-induced proliferation of CD19+ cells. In conclusion, we have demonstrated that neoplastic cells from patients with CLL have increased expression of p55 and p75 TNF receptors, and that both receptors mediate signal to proliferation. Furthermore, serum from CLL patients has elevated levels of soluble TNF receptors, which may counteract the proliferative effect of TNF.
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Waage, A., N. Liabakk, E. Lien, J. Lamvik y T. Espevik. "p55 and p75 tumor necrosis factor receptors in patients with chronic lymphocytic leukemia". Blood 80, n.º 10 (15 de noviembre de 1992): 2577–83. http://dx.doi.org/10.1182/blood.v80.10.2577.bloodjournal80102577.
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We studied the expression of the two tumor necrosis factor (TNF) receptors, p55 and p75, on B cells from patients with chronic lymphocytic leukemia (CLL), and the presence of soluble TNF receptors in serum. Expression of membrane-associated receptors was quantified by double labeling of peripheral blood mononuclear cells (PBMC) with monoclonal antibodies against CD19 and p55/p75 TNF receptors and flow cytometry. A high fraction of the CD19+ cells expressed the p55 receptor (44% +/- 34% [SD]) and p75 receptor (61% +/- 31%). In healthy controls, 0% to 1% of the CD19+ cells expressed the p55 receptor and 0% to 10% expressed the p75 receptor. Incubation of CD19+ cells with 10 ng/mL of TNF increased the incorporation of thymidine in 11 patients tested, and this was decreased to 65% (P < .05) by antibodies to the p55 receptor or the p75 receptor, and to 35% +/- 7% (P < .001) when both antibodies were combined. With an enzyme-linked immunoassay, we measured soluble TNF receptors in serum from CLL patients. The mean level of p55 receptors was increased to 12.9 +/- 8.9 ng/mL (P < .000001 v normal). The mean level of p75 receptors was increased to 13 +/- 24 ng/mL (P = .01 v normal). The membrane expression of the two receptors was positively correlated (r +/- 97, P < .01); however, there was no correlation between membrane expression and serum concentration of either receptor. Autologous serum containing high levels of soluble TNF receptors inhibited TNF-induced proliferation of CD19+ cells. In conclusion, we have demonstrated that neoplastic cells from patients with CLL have increased expression of p55 and p75 TNF receptors, and that both receptors mediate signal to proliferation. Furthermore, serum from CLL patients has elevated levels of soluble TNF receptors, which may counteract the proliferative effect of TNF.
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Ellis, James L. "Neurokinin receptors subserving bronchoconstriction". Canadian Journal of Physiology and Pharmacology 73, n.º 7 (1 de julio de 1995): 923–26. http://dx.doi.org/10.1139/y95-127.
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Tachykinin receptor subtypes were initially defined using agonist potency ratios for the endogenous ligands substance P (SP), neurokinin (NK) A, and NKB. On this basis it was suggested that there are three tachykinin receptor subtypes. These subtypes were designated NK1, NK2, and NK3, where SP is most potent at NK1 receptors, NKA is most potent at NK2 receptors, and NKB is most potent at NK3 receptors. Recently analogs of the endogenous ligands that show greater selectivity (about 1000-fold) for the different receptor subtypes have been developed. In addition selective antagonists, which are either nonpeptides or modified peptides, for the receptor subtypes have been developed. This minireview concentrates on the wealth of new knowledge concerning the tachykinin receptor subtypes subserving bronchoconstriction in several mammalian species, including man, provided by the use of these selective agonists and antagonists.Key words: neurokinins, bronchoconstriction, substance P, neurokinin A, receptor subtypes.
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Johnstone, Elizabeth K. M. y Kevin D. G. Pfleger. "Profiling novel pharmacology of receptor complexes using Receptor-HIT". Biochemical Society Transactions 49, n.º 4 (26 de agosto de 2021): 1555–65. http://dx.doi.org/10.1042/bst20201110.
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Many receptors are able to undergo heteromerisation, leading to the formation of receptor complexes that may have pharmacological profiles distinct from those of the individual receptors. As a consequence of this, receptor heteromers can be classed as new drug targets, with the potential for achieving greater specificity and selectivity over targeting their constituent receptors. We have developed the Receptor-Heteromer Investigation Technology (Receptor-HIT), which enables the detection of receptor heteromers using a proximity-based reporter system such as bioluminescence resonance energy transfer (BRET). Receptor-HIT detects heteromers in live cells and in real time, by utilising ligand-induced signals that arise from altered interactions with specific biomolecules, such as ligands or proteins. Furthermore, monitoring the interaction between the receptors and the specific biomolecules generates functional information about the heteromer that can be pharmacologically quantified. This review will discuss various applications of Receptor-HIT, including its use with different classes of receptors (e.g. G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and others), its use to monitor receptor interactions both intracellularly and extracellularly, and also its use with genome-edited endogenous proteins.
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Anders, Robert A., Sandra L. Arline, Jules J. E. Doré y Edward B. Leof. "Distinct Endocytic Responses of Heteromeric and Homomeric Transforming Growth Factor β Receptors". Molecular Biology of the Cell 8, n.º 11 (noviembre de 1997): 2133–43. http://dx.doi.org/10.1091/mbc.8.11.2133.
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Transforming growth factor β (TGFβ) family ligands initiate a cascade of events capable of modulating cellular growth and differentiation. The receptors responsible for transducing these cellular signals are referred to as the type I and type II TGFβ receptors. Ligand binding to the type II receptor results in the transphosphorylation and activation of the type I receptor. This heteromeric complex then propagates the signal(s) to downstream effectors. There is presently little data concerning the fate of TGFβ receptors after ligand binding, with conflicting reports indicating no change or decreasing cell surface receptor numbers. To address the fate of ligand-activated receptors, we have used our previously characterized chimeric receptors consisting of the ligand binding domain from the granulocyte/macrophage colony-stimulating factor α or β receptor fused to the transmembrane and cytoplasmic domain of the type I or type II TGFβ receptor. This system not only provides the necessary sensitivity and specificity to address these types of questions but also permits the differentiation of endocytic responses to either homomeric or heteromeric intracellular TGFβ receptor oligomerization. Data are presented that show, within minutes of ligand binding, chimeric TGFβ receptors are internalized. However, although all the chimeric receptor combinations show similar internalization rates, receptor down-regulation occurs only after activation of heteromeric TGFβ receptors. These results indicate that effective receptor down-regulation requires cross-talk between the type I and type II TGFβ receptors and that TGFβ receptor heteromers and homomers show distinct trafficking behavior.
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Salmon, J. E., N. Brogle, C. Brownlie, J. C. Edberg, R. P. Kimberly, B. X. Chen y B. F. Erlanger. "Human mononuclear phagocytes express adenosine A1 receptors. A novel mechanism for differential regulation of Fc gamma receptor function." Journal of Immunology 151, n.º 5 (1 de septiembre de 1993): 2775–85. http://dx.doi.org/10.4049/jimmunol.151.5.2775.
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Abstract Using monoclonal anti-adenosine A1 receptor antibodies that bind the A1 receptor ligand binding site, we demonstrate that A1 receptors are expressed on cultured monocytes and rheumatoid synovial fluid mononuclear phagocytes. This finding is associated with the acquisition of reactivity with selective adenosine A1 receptor agonists and is temporally coordinated with the induction of adenosine A2 receptors on cultured monocytes. In a rapid, concentration-dependent fashion, these two distinct adenosine receptors modulate Fc gamma receptor-mediated phagocytosis, a response critical to the pathogenesis of immune complex diseases. Occupancy of A1 receptors by N6-cyclopentyladenosine (an A1-specific adenosine analogue) or mAb AA1 (an anti-A1 mAb) results in a potent stimulation that is blocked by adenosine receptor antagonists. This A1 receptor-induced enhancement of Fc gamma receptor-mediated phagocytosis is a consequence of preferential augmentation of Fc gamma RI function, suggesting distinct mechanisms for receptor-effector coupling of Fc gamma receptor families. In contrast, ligation of A2 receptors by A2-specific agonists decreases Fc gamma receptor-mediated phagocytosis in cultured monocytes. The opposing effects of adenosine A1 and A2 receptors allow for a concentration-dependent feed-back loop that responds more rapidly than effects elicited by other endogenous modulators. Low concentrations of adenosine are proinflammatory providing enhanced Fc gamma receptor function via A1 receptors, whereas higher concentrations that can occur with tissue damage are anti-inflammatory providing inhibition via A2 receptors. This rapid and potent modulation of Fc gamma receptor-mediated function suggests that adenosine is an important local regulator of the inflammatory response.
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Agnati, Luigi F., Giuseppina Leo, Susanna Genedani, Diego Guidolin, Nicola Andreoli y Kjell Fuxe. "Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease". Scientific World JOURNAL 7 (2007): 1073–81. http://dx.doi.org/10.1100/tsw.2007.166.
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It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers), but clusters of receptors (receptor mosaics), altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.
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Kashles, O., Y. Yarden, R. Fischer, A. Ullrich y J. Schlessinger. "A dominant negative mutation suppresses the function of normal epidermal growth factor receptors by heterodimerization". Molecular and Cellular Biology 11, n.º 3 (marzo de 1991): 1454–63. http://dx.doi.org/10.1128/mcb.11.3.1454-1463.1991.
Texto completoResumen
Recent studies provide evidence that defective receptors can function as a dominant negative mutation suppressing the action of wild-type receptors. This causes various diminished responses in cell culture and developmental disorders in murine embryogenesis. Here, we describe a model system and a potential mechanism underlying the dominant suppressing response caused by defective epidermal growth factor (EGF) receptors. We used cultured 3T3 cells coexpressing human wild-type receptors and an inactive deletion mutant lacking most of the cytoplasmic domain. When expressed alone, EGF was able to stimulate the dimerization of either wild-type or mutant receptors in living cells as revealed by chemical covalent cross-linking experiments. In response to EGF, heterodimers and homodimers of wild-type and mutant receptors were observed in cells coexpressing both receptor species. However, only homodimers of wild-type EGF receptors underwent EGF-induced tyrosine autophosphorylation in living cells. These results indicate that the integrity of both receptor moieties within receptor dimers is essential for kinase activation and autophosphorylation. Moreover, the presence of mutant receptors in cells expressing wild-type receptors diminished the number of high-affinity binding sites for EGF, reduced the rate of receptor endocytosis and degradation, and diminished biological signalling via EGF receptors. We propose that heterodimerization with defective EGF receptors functions as a dominant negative mutation suppressing the activation and response of normal receptors by formation of unproductive heterodimers.
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Kashles, O., Y. Yarden, R. Fischer, A. Ullrich y J. Schlessinger. "A dominant negative mutation suppresses the function of normal epidermal growth factor receptors by heterodimerization." Molecular and Cellular Biology 11, n.º 3 (marzo de 1991): 1454–63. http://dx.doi.org/10.1128/mcb.11.3.1454.
Texto completoResumen
Recent studies provide evidence that defective receptors can function as a dominant negative mutation suppressing the action of wild-type receptors. This causes various diminished responses in cell culture and developmental disorders in murine embryogenesis. Here, we describe a model system and a potential mechanism underlying the dominant suppressing response caused by defective epidermal growth factor (EGF) receptors. We used cultured 3T3 cells coexpressing human wild-type receptors and an inactive deletion mutant lacking most of the cytoplasmic domain. When expressed alone, EGF was able to stimulate the dimerization of either wild-type or mutant receptors in living cells as revealed by chemical covalent cross-linking experiments. In response to EGF, heterodimers and homodimers of wild-type and mutant receptors were observed in cells coexpressing both receptor species. However, only homodimers of wild-type EGF receptors underwent EGF-induced tyrosine autophosphorylation in living cells. These results indicate that the integrity of both receptor moieties within receptor dimers is essential for kinase activation and autophosphorylation. Moreover, the presence of mutant receptors in cells expressing wild-type receptors diminished the number of high-affinity binding sites for EGF, reduced the rate of receptor endocytosis and degradation, and diminished biological signalling via EGF receptors. We propose that heterodimerization with defective EGF receptors functions as a dominant negative mutation suppressing the activation and response of normal receptors by formation of unproductive heterodimers.
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Wang, Kemo y Jian Liu. "Needling Sensation Receptor of an Acupoint Supplied by the Median Nerve - Studies of their Electro-Physiological Characteristics". American Journal of Chinese Medicine 17, n.º 03n04 (enero de 1989): 145–55. http://dx.doi.org/10.1142/s0192415x89000231.
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We classified 50 receptor units from 10 acupoints supplied by the medium nerve. It was found that the needling stimulation mostly excited slowly adapting receptors and that the classification of acupoint receptors related closely to their location. For example, the Shanyang, Zhongchong, Shaoshang acupoints in the skin needling sensation receptors are touch or pressure receptor units; the receptors of Neiguan, Yuji, etc.; the acupoints located in deep tissue with abundant muscles, are mostly muscle spindles; the Daling acupoint might be a colgi tendon and/or pressure receptor unit. Besides a significant receptor, an acupoint contains one or more needling sensation receptor. The receptors and the afferent fibers of acupoints take part in forming and maintaining the needling sensations.
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Woodcock, E. A., S. L. Land, R. K. Andrews, M. Linsenmeyer y D. M. Woodcock. "A low-affinity, low-molecular-mass endothelin-A receptor in neonatal rat heart". Biochemical Journal 304, n.º 1 (15 de noviembre de 1994): 113–19. http://dx.doi.org/10.1042/bj3040113.
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Endothelin receptors with endothelin-A (ETa) specificity were present in neonatal rat ventricle. However, in both receptor-binding studies and studies of inositol phosphate accumulation, these receptors had lower affinity for endothelin-1 than ETa receptors on isolated neonatal cardiomyocytes or adult left atria. Receptors in the three myocardial preparations were cross-linked to 125I-endothelin-1 and their molecular masses measured using SDS/PAGE. Receptors on left atria and neonatal cardiomyocytes had the expected molecular mass of 48 kDa, whereas the receptors in neonatal ventricle were smaller (38 kDa). Despite this, neonatal ventricles contained ETa receptor mRNA which was not different in size from that in the isolated cells (4.5 kb). Thus the 38 kDa ETa receptor present in neonatal ventricle appears to be transcribed from full-length ETa receptor mRNA and is possibly formed by processing of the 48 kDa receptor.
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Liu, R. y J. N. Livingston. "Association of the insulin receptor and phosphatidylinositol 3-kinase requires a third component". Biochemical Journal 297, n.º 2 (15 de enero de 1994): 335–42. http://dx.doi.org/10.1042/bj2970335.
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We have studied the interactions between the insulin receptor and PtdIns 3-kinase by a reconstitution system in vitro composed of highly purified PtdIns 3-kinase from rat liver and highly purified insulin receptors bound to insulin-agarose or to antibodies against insulin receptors. As a positive control, receptors for platelet-derived growth factor, which bind and phosphorylate PtdIns 3-kinase, were studied in parallel with insulin receptors. Our results indicate that the insulin receptor, regardless of its phosphorylation state, does not directly associate with purified PtdIns 3-kinase, whereas the autophosphorylated receptor does associate with PtdIns 3-kinase present in the crude CHO-cell lysate. Also, we could not detect phosphorylation of PtdIns 3-kinase by the insulin receptor, even through the receptor readily underwent autophosphorylation and phosphorylated an insulin-receptor substrate, poly(Glu-Tyr) (4:1). These findings argue that one or more cytosolic components link the receptor and the enzyme. Insulin-receptor substrate-1 (IRS-1) was evaluated as a potential linking protein. In the absence of ATP, IRS-1 did not facilitate the coupling of the phosphorylated insulin receptor to PtdIns 3-kinase. Thus IRS-1 is unlikely to be the component in crude CHO-cell lysate that couples PtdIns 3-kinase to the phosphorylated insulin receptor. However, the addition of ATP, which allows phosphorylation of IRS-1 by the insulin receptor, also enhances the coupling of PtdIns 3-kinase to the insulin receptor. In support of this idea, immunoprecipitates of IRS-1 from insulin-treated CHO cells were found to contain both the insulin receptor and PtdIns 3-kinase. In conclusion, the insulin receptor does not appear to phosphorylate or bind directly to PtdIns 3-kinase, regardless of the receptor's state of phosphorylation. Association of PtdIns 3-kinase with the insulin receptor is mediated by one or more components, one of which may involve an unidentified factor in cell lysate and another that apparently involves phosphorylated IRS-1.
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Gurevich, Eugenia V. y Vsevolod V. Gurevich. "GRKs as Modulators of Neurotransmitter Receptors". Cells 10, n.º 1 (31 de diciembre de 2020): 52. http://dx.doi.org/10.3390/cells10010052.
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Many receptors for neurotransmitters, such as dopamine, norepinephrine, acetylcholine, and neuropeptides, belong to the superfamily of G protein-coupled receptors (GPCRs). A general model posits that GPCRs undergo two-step homologous desensitization: the active receptor is phosphorylated by kinases of the G protein-coupled receptor kinase (GRK) family, whereupon arrestin proteins specifically bind active phosphorylated receptors, shutting down G protein-mediated signaling, facilitating receptor internalization, and initiating distinct signaling pathways via arrestin-based scaffolding. Here, we review the mechanisms of GRK-dependent regulation of neurotransmitter receptors, focusing on the diverse modes of GRK-mediated phosphorylation of receptor subtypes. The immediate signaling consequences of GRK-mediated receptor phosphorylation, such as arrestin recruitment, desensitization, and internalization/resensitization, are equally diverse, depending not only on the receptor subtype but also on phosphorylation by GRKs of select receptor residues. We discuss the signaling outcome as well as the biological and behavioral consequences of the GRK-dependent phosphorylation of neurotransmitter receptors where known.
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Yuzaki, Michisuke y John A. Connor. "Characterization of l-Homocysteate–Induced Currents in Purkinje Cells From Wild-Type and NMDA Receptor Knockout Mice". Journal of Neurophysiology 82, n.º 5 (1 de noviembre de 1999): 2820–26. http://dx.doi.org/10.1152/jn.1999.82.5.2820.
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l-Homocysteic acid (HCA), an endogenous excitatory amino acid in the mammalian CNS, potently activates N-methyl-d-aspartate (NMDA) receptors in hippocampal neurons. However, the responses to HCA in Purkinje cells, which lack functional NMDA receptors, have been largely unexplored: HCA may activate conventional non-NMDA receptors by its mixed agonistic action on both NMDA and non-NMDA receptors, or it may activate a novel non-NMDA receptor that has high affinity for HCA. To test these possibilities, we compared the responses to HCA in cultured Purkinje cells with those in hippocampal neurons by using the whole cell patch-clamp technique. To clearly isolate HCA responses mediated by non-NMDA receptors, we complemented pharmacological methods by using neurons from mutant mice (NR−/−) that lack functional NMDA receptors. A moderate dose of HCA (100 μM) induced substantial responses in Purkinje cells. These responses were blocked by non-NMDA receptor antagonists but were insensitive to NMDA receptor antagonists. HCA also activated responses mediated by non-NMDA receptors in both wild-type and NR1−/− hippocampal neurons. HCA responses in Purkinje cells had a pharmacological profile (EC50 and Hill coefficient) very similar to that of non-NMDA receptor components of HCA responses in hippocampal neurons. Moreover, the amplitude of the non-NMDA receptor component of HCA responses was directly correlated with that of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)– and kainate-induced responses in both types of neurons. Finally, in both types of neurons, HCA currents mediated by non-NMDA receptors were potently blocked by the AMPA receptor antagonist GYKI52466. These findings indicate that HCA-activated AMPA receptors in Purkinje cells are similar to those in hippocampal neurons and that there is no distinct HCA-preferring receptor in Purkinje cells. We also found that in hippocampal neurons, the EC50s of HCA for non-NMDA receptors and for NMDA receptors were more similar than originally reported; this finding indicates that HCA is similar to other mixed agonists, such as glutamate. HCA responses may appear to be selective at NMDA receptors in cells that express these receptors, such as hippocampal neurons; in cells that express few functional NMDA receptors, such as Purkinje cells, HCA may appear to be selective at non-NMDA receptors.