International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors (original) (raw)
Related papers
Muscarinic Receptors—Characterization, coupling and function
Pharmacology & Therapeutics, 1993
At least five muscarinic receptor genes have been cloned and expressed. Muscarinic receptors act via activation of G proteins: ml, m3 and m5 muscarinic receptors couple to stimulate phospholipase C, while m2 and m4 muscarinic receptors inhibit adenylyl cyclase. This review describes the localization, pharmacology and function of the five muscarinic receptor subtypes. The actions of muscarinic receptors on the heart, smooth muscle, glands and on neurons (both presynaptic and postsynaptic) in the autonomic nervous system and the central nervous system are analyzed in terms of subtypes, biochemical mechanisms and effects on ion channels, including K + channels and Ca 2+ channels. References
Antagonist Discrimination Between Ganglionic and Ileal Muscarinic Receptors
British Journal of Pharmacology, 1997
The effects of four antagonists on the depolarization of isolated superior cervical ganglia and the contraction of isolated ileal segments of the rat were compared. pA2 values estimated from Schild plots indicated significantly higher affinities of stercuronium (x 100) and pirenzepine ( x 23) and a significantly lower affinity of 4-diphenylacetoxy-N-methylpiperidine methiodide ( x 0.39) for the ganglion than for the ileum. The affinities of N-methylscopolamine for the two tissues were not significantly different. It is concluded that the two types of muscarinic receptor are not identical.
Direct binding studies on ileal and cardiac muscarinic receptors
British Journal of Pharmacology, 1987
Functional studies have indicated that muscarinic receptors in cardiac tissue differ from those in the ileum. In the present study ileal and cardiac muscarinic receptors identified by [3H]-N-methyl scopolamine ([3H]-NMS) were characterized and the selectivity of currently available ileal and atrial selective antagonists determined. 2 In terms of the current functional classification of muscarinic receptors both ileal and cardiac muscarinic receptors were of the M2 subtype based upon their low affinity for pirenzepine. 3 Cyclohexylphenyl(2-piperidinoethyl)silanol (CPPS), a highly ileal selective antagonist in functional studies, was unable to distinguish between ileal and atrial muscarinic receptors identified in binding studies. Furthermore, although AF-DX 116 and dicyclomine were able to differentiate atrial and ileal muscarinic receptors, neither compound was more than 2 fold selective. These data indicate that it is not possible to subclassify ileal and atrial muscarinic receptors using direct ligand binding studies with these antagonists. 4 In circular ileal smooth muscle, apparent heterogeneity of the M2 muscarinic receptor population was observed. Thus AF-DX 116 identified two populations of sites with affinities differing by 30 fold. These two populations of M2 muscarinic receptors may represent the typical M2 muscarinic receptors identified in cardiac tissue and the more recently discovered 'gland type' M2 muscarinic receptors. 5 The circular ileal smooth muscle tissue homogenate was able to decrease dramatically the apparent affinity of adiphenine. This activity, which appeared to result from a phenylmethylsulphonylfluoride (PMSF) sensitive protease effect, should be considered when conducting studies using this tissue preparation and compounds of similar structure to adiphenine.
Interaction of agonists and selective antagonists with gastric smooth muscle muscarinic receptors
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
The interaction of cholinergic agonists and antagonists with smooth muscle muscarinic receptors has been investigated by measurement of displacement of the muscarinic antagonist [3H]QNB (quinuclidinyl benzilate) in membranes prepared from toad stomach. The binding of [3H]QNB was saturable, reversible and of high affinity (Ko = 423 pM). The muscarinic receptor subtypes present in gastric smooth muscle were classified by determining the relative affinities for the selective antagonists pirenzepine (M0, AF-DX 116 (M2) and 4-DAMP (M3). The results from these studies indicate the presence of a heterogeneous population of muscarinic receptor subtypes, with a majority (88 %) exhibiting characteristics of M3 receptors and a much smaller population (12%) exhibiting characteristics of M2 receptors. The binding curve for the displacement of [3H]QNB binding by the agonist oxotremorine was complex and was consistent with presence of two affinity states: 24% of the receptors had a high affinity (KD = 4.7 nM) for oxotremorine and 76% displayed nearly a 1,000-fold lower affinity (KD = 4.4 gM). When oxotremorine displacement of [3H]QNB binding was determined in the presence GTPTS, high affinity binding was abolished, indicating that high affinity agonist binding may represent receptors coupled to G proteins. Moreover, pertussis toxin pretreatment of membranes also abolished high affinity agonist binding, indicating that the muscarinic receptors are coupled to pertussis toxin-sensitive G proteins. Reaction of smooth muscle membranes with pertussis toxin in the presence [32p]NAD caused the [32p]-labelling of a 40 kD protein that may represent the ~ subunit(s) of G proteins that are known to be NAD-ribosylated by the toxin. We conclude that both M3 and M: receptors may be coupled to G proteins in a pertussis-sensitive manner.
European Journal of Pharmacology, 1994
The present study examined the effects of a series of tricyclic muscarinic receptor antagonists on muscarinic receptors present in the guinea-pig ileum, both in vitro and in vivo. The selectivity profiles of these antagonists and that of atropine were determined by their affinity for cortical muscarinic M1, cardiac M 2 and submandibular M 3 receptors and for m4 receptors expressed in CHO cells. The compounds pirenzepine, UH-AH 37, AQ-RA 391 and AQ-RA 618 possessed high affinity (pK i 7.94-8.22) for muscarinic M t receptors. Pirenzepine exhibited the most pronounced muscarinic M x selectivity. AF-DX 384 and AQ-RA 741 possessed an approximately 10-fold higher affinity for the cardiac muscarinic M e receptor than AF-DX 116. However, both compounds also exhibited high affinity for muscarinic m4 receptors. High affinity for muscarinic M 3 and m4 receptors was observed for UH-AH 37, AQ-RA 391 and AQ-RA 681. The antagonists were then tested for their interaction with the muscarinic receptors which are responsible for the methacholine-induced contraction of longitudinal muscle in vitro, circular muscle in vivo and muscarinic receptors which mediate the distension-evoked ascending reflex contraction of circular muscle in vitro. Compounds showing high affinity for muscarinic M 3 receptors (e.g. AQ-RA 618) were the most potent antagonists in the functional experiments. Comparison of the binding displacement data with the functional results indicates that the effects of methacholine on the longitudinal and circular muscle of the guinea-pig ileum were predominantly mediated by muscarinic M3-type receptors. In contrast, the correlation between muscarinic M 2 receptor affinity and antagonism of muscarinic receptors in the ileum was very weak.
Determination of the muscarinic receptor subtype mediating vasodilatation
British Journal of Pharmacology, 1985
The muscarinic receptor mediating vasodilatation of the rabbit aorta and dog femoral artery has been assessed using muscarinic antagonists. With the exception of pirenzepine, the antagonist affinities were similar to those reported for the ileal receptors and dissimilar to those reported for the atrial receptors. Pirenzepine exhibited an affinity (7.54) intermediate between that reported for the CNS receptors (8.4) and that reported for the ileal receptors (6.77). This value for pirenzepine was confirmed using acetylcholine as the agonist and using the dog femoral artery as the vascular tissue. It is concluded that the muscarinic receptor profile mediating vasodilatation is not easily accommodated into the current receptor classification.