scholarly journals Distribution and function of the muscarinic receptor subtypes in the cardiovascular system

2018 ◽  
Vol 50 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Hannah C. Saternos ◽  
Daniyah A. Almarghalani ◽  
Hayley M. Gibson ◽  
Mahmood A. Meqdad ◽  
Raymond B. Antypas ◽  
...  
Keyword(s):  
Animal Models ◽  
Cardiovascular System ◽  
Muscarinic Receptor ◽  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Receptor Subtypes ◽  
Parasympathetic System ◽  
Knockout Animal ◽  
And Function

Muscarinic acetylcholine receptors belong to the G protein-coupled receptor superfamily and are widely known to mediate numerous functions within the central and peripheral nervous system. Thus, they have become attractive therapeutic targets for various disorders. It has long been known that the parasympathetic system, governed by acetylcholine, plays an essential role in regulating cardiovascular function. Unfortunately, due to the lack of pharmacologic selectivity for any one muscarinic receptor, there was a minimal understanding of their distribution and function within this region. However, in recent years, advancements in research have led to the generation of knockout animal models, better antibodies, and more selective ligands enabling a more thorough understanding of the unique role muscarinic receptors play in the cardiovascular system. These advances have shown muscarinic receptor 2 is no longer the only functional subtype found within the heart and muscarinic receptors 1 and 3 mediate both dilation and constriction in the vasculature. Although muscarinic receptors 4 and 5 are still not well characterized in the cardiovascular system, the recent generation of knockout animal models will hopefully generate a better understanding of their function. This mini review aims to summarize recent findings and advances of muscarinic involvement in the cardiovascular system.

scholarly journals Imaging Muscarinic Cholinergic Receptors in Human Brain in vivo with SPECT, [123I]4-Iododexetimide, and [123I]4-Iodolevetimide

1992 ◽  
Vol 12 (4) ◽  
pp. 562-570 ◽  
Author(s):  
Hans W. Müller-Gärtner ◽  
Alan A. Wilson ◽  
Robert F. Dannals ◽  
Henry N. Wagner ◽  
J. James Frost
Keyword(s):  
Human Brain ◽  
Muscarinic Receptor ◽  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Brain Regions ◽  
Muscarinic Acetylcholine Receptors ◽  
Emission Computed Tomography ◽  
Nonspecific Binding ◽  
Muscarinic Acetylcholine

A method to image muscarinic acetylcholine receptors (muscarinic receptors) noninvasively in human brain in vivo was developed using [123I]4-iododexetimide ([123I]IDex), [123I]4-iodolevetimide ([123I]ILev), and single photon emission computed tomography (SPECT). [123I]IDex is a high-affinity muscarinic receptor antagonist. [123I]ILev is its pharmacologically inactive enantiomer and measures nonspecific binding of [123I]IDex in vitro. Regional brain activity after tracer injection was measured in four young normal volunteers for 24 h. Regional [123I]IDex and [123I]ILev activities were correlated early after injection, but not after 1.5 h. [123I]IDex activity increased over 7–12 h in neocortex, neostriatum, and thalamus, but decreased immediately after the injection peak in cerebellum. [123I]IDex activity was highest in neostriatum, followed in rank order by neocortex, thalamus, and cerebellum. [123I]IDex activity correlated with muscarinic receptor concentrations in matching brain regions. In contrast, [123I]ILev activity decreased immediately after the injection peak in all brain regions and did not correspond to muscarinic receptor concentrations. [123I]IDex activity in neocortex and neostriatum during equilibrium was six to seven times higher than [123I]ILev activity. The data demonstrate that [123I]IDex binds specifically to muscarinic receptors in vivo, whereas [123I]ILev represents the nonspecific part of [123I]IDex binding. Subtraction of [123I]ILev from [123I]IDex images on a pixel-by-pixel basis therefore reflects specific [123I]IDex binding to muscarinic receptors. Owing to its high specific binding, [123I]IDex has the potential to measure small changes in muscarinic receptor characteristics in vivo with SPECT. The use of stereoisomerism directly to measure nonspecific binding of [123I]IDex in vivo may reduce complexity in modeling approaches to muscarinic acetylcholine receptors in human brain.

scholarly journals Role of M1, M3, and M5 muscarinic acetylcholine receptors in cholinergic dilation of small arteries studied with gene-targeted mice

2011 ◽  
Vol 300 (5) ◽  
pp. H1602-H1608 ◽  
Author(s):  
Adrian Gericke ◽  
Jan J. Sniatecki ◽  
Veronique G. A. Mayer ◽  
Evgeny Goloborodko ◽  
Andreas Patzak ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscarinic Receptor ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Receptor Subtypes ◽  
Wild Type ◽  
Luminal Diameter ◽  
Small Arteries ◽  
Muscarinic Acetylcholine

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.

Steroids as the novel class of high-affinity allosteric modulators of muscarinic receptors

2021 ◽  
Author(s):  
Eva Dolejší ◽  
Eszter Szánti-Pintér ◽  
Nikolai Chetverikov ◽  
Dominik Nelic ◽  
Alena Randáková ◽  
...  
Keyword(s):  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Allosteric Modulators ◽  
The Novel ◽  
Stress Control ◽  
Structure Activity ◽  
G Protein Coupled

Abstract The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone, and some neurosteroids bound to muscarinic receptors with an affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol-binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.

Location and quantification of muscarinic receptor subtypes in rat pons: implications for REM sleep generation

1997 ◽  
Vol 273 (3) ◽  
pp. R896-R904 ◽  
Author(s):  
H. A. Baghdoyan
Keyword(s):  
Muscarinic Receptor ◽  
Reticular Formation ◽  
Muscarinic Receptors ◽  
Rem Sleep ◽  
Binding Sites ◽  
Reticular Nucleus ◽  
Homogeneous Distribution ◽  
Receptor Subtypes ◽  
Pontine Reticular Formation ◽  
Muscarinic Receptor Subtypes

Microinjecting cholinomimetics into the pontine reticular formation produces a state that resembles natural rapid eye movement (REM) sleep. Evocation of this REM sleeplike states is anatomically site dependent within the pons and is mediated by muscarinic receptors. The cellular and molecular mechanisms underlying cholinergic REM sleep generation and muscarinic receptor subtype involvement remain to be specified. This study tested the hypothesis that muscarinic receptor subtypes are differentially distributed within the oral and caudal divisions of rat pontine reticular nucleus. In vitro receptor autoradiography was used to localize and quantify M1, M2, and M3 binding sites in the pontine reticular formation and in pontine brain stem regions known to regulate REM sleep. M1-M3 binding sites were present in some REM sleep-related nuclei, such as dorsal raphe and locus ceruleus. The pontine reticular formation was found to have a homogeneous distribution of M2 binding sites across its rostral to caudal extent, indicating that anatomic specificity of cholinergic REM sleep induction cannot be accounted for by a differential density of muscarinic receptors.

RT-PCR reveals muscarinic acetylcholine receptor mRNA in the pre-Bötzinger complex

2001 ◽  
Vol 281 (6) ◽  
pp. L1420-L1424 ◽  
Author(s):  
Jiunu Lai ◽  
Xuesi M. Shao ◽  
Richard W. Pan ◽  
Edward Dy ◽  
Cindy H. Huang ◽  
...  
Keyword(s):  
Muscarinic Receptor ◽  
Muscarinic Receptors ◽  
Respiratory Rhythm ◽  
Pcr Amplification ◽  
Cholinergic Receptor ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Muscarinic Receptor Subtypes ◽  
Rt Pcr ◽  
Bötzinger Complex

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.

scholarly journals Classifying neuronal subclasses of the cerebellum through constellation pharmacology

2016 ◽  
Vol 115 (2) ◽  
pp. 1031-1042 ◽  
Author(s):  
Kigen J. Curtice ◽  
Lee S. Leavitt ◽  
Kevin Chase ◽  
Shrinivasan Raghuraman ◽  
Martin P. Horvath ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Gaba Receptors ◽  
Acetylcholine Receptors ◽  
Granule Cells ◽  
Functional Expression ◽  
Muscarinic Acetylcholine Receptors ◽  
Receptor Subtypes ◽  
Mouse Cerebellum ◽  
The Brain

A pressing need in neurobiology is the comprehensive identification and characterization of neuronal subclasses within the mammalian nervous system. To this end, we used constellation pharmacology as a method to interrogate the neuronal and glial subclasses of the mouse cerebellum individually and simultaneously. We then evaluated the data obtained from constellation-pharmacology experiments by cluster analysis to classify cells into neuronal and glial subclasses, based on their functional expression of glutamate, acetylcholine, and GABA receptors, among other ion channels. Conantokin peptides were used to identify N-methyl-d-aspartate (NMDA) receptor subtypes, which revealed that neurons of the young mouse cerebellum expressed NR2A and NR2B NMDA receptor subunits. Additional pharmacological tools disclosed differential expression of α-amino-3-hydroxy-5-methyl-4-isoxazloepropionic, nicotinic acetylcholine, and muscarinic acetylcholine receptors in different neuronal and glial subclasses. Certain cell subclasses correlated with known attributes of granule cells, and we combined constellation pharmacology with genetically labeled neurons to identify and characterize Purkinje cells. This study illustrates the utility of applying constellation pharmacology to classify neuronal and glial subclasses in specific anatomical regions of the brain.

scholarly journals Characterization of Prejunctional Muscarinic Receptors: Effects on the Release of VIP and Functional Responses and Receptor Expression in the Ovine Submandibular Gland

2009 ◽  
Vol 2009 ◽  
pp. 1-6
Author(s):  
Anders T. Ryberg ◽  
Ondrej Soukup ◽  
Gunnar Tobin
Keyword(s):  
Electrical Stimulation ◽  
Submandibular Gland ◽  
Muscarinic Receptor ◽  
Muscarinic Receptors ◽  
Receptor Expression ◽  
Receptor Subtypes ◽  
Chorda Tympani Nerve ◽  
Functional Responses ◽  
Stimulation Of

In the in vivo experiments on anaesthetized sheep, it was presently examined whether muscarinic receptor antagonists with diverse selectivity affect the release of VIP in response to electrical stimulation of the parasympathetic chorda tympanic nerve differently, and if the changes in the release could be associated to altered secretory and vasodilator responses. The location of the muscarinic receptor subtypes was examined also. In the experiments, blood was collected out of the submandibular venous drainage before and during electrical stimulation of chorda tympani nerve in the absence and presence either of pirenzepine or methoctramine. While metchoctramine increased the output of protein, pirenzepine inhibited flow of saliva and increased protein output, vasodilatation, and VIP output. In morphological examinations, the inhibitory muscarinic M4 receptor occurred interacinarily in the gland. It is concluded that prejunctional muscarinic receptors, most likely of the M4 subtype, exert inhibitory modulation of the parasympathetic release of VIP in the ovine submandibular gland.

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