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Muscarinic M1 (muscarinic + m1)
Selected AbstractsMuscarinic receptor subtypes in neuronal and non-neuronal cholinergic functionAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2006R. M. Eglen Summary 1 Muscarinic M1,M5 receptors mediate the metabotropic actions of acetylcholine in the nervous system. A growing body of data indicate they also mediate autocrine functions of the molecule. The availability of novel and selective muscarinic agonists and antagonists, as well as in vivo gene disruption techniques, has clarified the roles of muscarinic receptors in mediating both functions of acetylcholine. 2 Selective M1 agonists or mixed M1 agonists/M2 antagonists may provide an approach to the treatment of cognitive disorders, while M3 antagonism, or mixed M2/M3 antagonists, are approved for the treatment of contractility disorders including overactive bladder and chronic obstructive pulmonary disease. Preclinical data suggest that selective agonism of the M4 receptor will provide novel anti-nociceptive agents, while therapeutics-based upon agonism or antagonism of the muscarinic M5 receptor have yet to be reported. 3 The autocrine functions of muscarinic receptors broadly fall into two areas , control of cell growth or proliferation and mediation of the release of chemical mediators from epithelial cells, ultimately causing muscle relaxation. The former particularly are involved in embryological development, oncogenesis, keratinocyte function and immune responsiveness. The latter regulate contractility of smooth muscle in the vasculature, airways and urinary bladder. 4 Most attention has focused on muscarinic M1 or M3 receptors which mediate lymphocyte immunoresponsiveness, cell migration and release of smooth muscle relaxant factors. Muscarinic M4 receptors are implicated in the regulation of keratinocyte adhesion and M2 receptors in stem cell proliferation and development. Little data are available concerning the M5 receptor, partly due to the difficulties in defining the subtype pharmacologically. 5 The autocrine functions of acetylcholine, like those in the nervous system, involve activation of several muscarinic receptor subtypes. Consequently, the role of these subtypes in autocrine, as well neuronal cholinergic systems, significantly expands their importance in physiology and pathophysiology. [source] N-Homolupinanoyl and N-(,-Lupinylthio)alkanoyl Derivatives of Some Tricyclic Systems as Ligands for Muscarinic M1 and M2 Receptor Subtypes.CHEMINFORM, Issue 4 2004Bruno Tasso Abstract For Abstract see ChemInform Abstract in Full Text. [source] Modulation by adenosine of both muscarinic M1 -facilitation and M2 -inhibition of [3H]-acetylcholine release from the rat motor nerve terminalsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2002Laura Oliveira Abstract The crosstalk between adenosine and muscarinic autoreceptors regulating evoked [3H]-acetylcholine ([3H]-ACh) release was investigated on rat phrenic nerve-hemidiaphragm preparations. Motor nerve terminals possess facilitatory M1 and inhibitory M2 autoreceptors that can be activated by McN-A-343 (1,30 µm) and oxotremorine (0.3,100 µm), respectively. The muscarinic receptor antagonist, dicyclomine (3 nm,10 µm), caused a biphasic (inhibitory/facilitatory) effect, indicating that M1 -facilitation prevails during 5 Hz stimulation trains. Concomitant activation of AF,DX 116-sensitive M2 receptors was partially attenuated, as pretreatment with M1 antagonists, muscarinic toxin 7 (MT-7, 0.1 nm) and pirenzepine (1 nm), significantly enhanced inhibition by oxotremorine. Activation of A2A -adenosine receptors with CGS 21680C (2 nm) (i) potentiated oxotremorine inhibition, and (ii) shifted McN-A-343-induced facilitation into a small inhibitory effect. Conversely, the A1 -receptor agonist, R- N6 -phenylisopropyl adenosine (R-PIA, 100 nm), attenuated the inhibitory effect of oxotremorine, without changing facilitation by McN-A-343. Synergism between A2A and M2 receptors is regulated by a reciprocal interaction with facilitatory M1 receptors, which may be prevented by pirenzepine (1 nm). During 50 Hz-bursts, facilitation (M1) of [3H]-ACh release by McN-A-343 disappeared, while the inhibitory (M2) effect of oxotremorine became predominant. This muscarinic shift results from the interplay with A2A receptors, as it was precluded by the selective A2A receptor antagonist, ZM 241385 (10 nm). In conclusion, when the muscarinic M1 positive feedback loop is fully operative, negative regulation of ACh release is mediated by adenosine A1 receptors. During high frequency bursts, tonic activation of A2A receptors promotes M2 autoinhibition by braking the M1 receptor operated counteraction. [source] Involvement of ,, Subunits of Gq/11 in Muscarinic M1 Receptor Potentiation of Corticotropin-Releasing Hormone-Stimulated Adenylyl Cyclase Activity in Rat Frontal CortexJOURNAL OF NEUROCHEMISTRY, Issue 1 2000Maria C. Olianas Abstract : In the present study, we investigated the involvement of ,, subunits of Gq/11 in the muscarinic M1 receptor-induced potentiation of corticotropin-releasing hormone (CRH)-stimulated adenylyl cyclase activity in membranes of rat frontal cortex. Tissue exposure to either one of two ,, scavengers, the QEHA fragment type II adenylyl cyclase and the GDP-bound form of the , subunit of transducin, inhibited the muscarinic M1 facilitatory effect. Moreover, like acetylcholine (ACh), exogenously added ,, subunits of transducin potentiated the CRH-stimulated adenylyl cyclase activity, and this effect was not additive with that elicited by ACh. Western blot analysis indicated the expression in frontal cortex of both type II and type IV adenylyl cyclases, two isoforms stimulated by ,, subunits in synergism with activated Gs. The M1 receptor-induced enhancement of the adenylyl cyclase response to CRH was counteracted by the Gq/11 antagonist GpAnt-2A but not by GpAnt-2, a preferential Gi/o antagonist. In addition, the muscarinic facilitatory effect was inhibited by membrane preincubation with antiserum directed against the C terminus of the , subunit of Gq/11, whereas the same treatment with antiserum against either Gi1/2 or Go was without effect. These data indicate that in membranes of rat frontal cortex, activation of muscarinic M1 receptors potentiates CRH-stimulated adenylyl cyclase activity through ,, subunits of Gq/11. [source] Decreased density of muscarinic receptors in the superior temporal gyrusin schizophreniaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2005Chao Deng Abstract Recent studies have indicated that muscarinic receptors are involved in the pathophysiology in schizophrenia, particularly in cognitive deficits. The superior temporal gyrus (STG) is an area that has also been strongly implicated in the pathophysiology of schizophrenia. Therefore, in this study, we investigated the binding density of two muscarinic antagonists, [3H]pirenzepine and [3H]AF-DX384, in the STG of schizophrenia patients compared with controls. A significant decrease (44% in the superficial layers and 48% in the deep layers, P < 0.01) in binding density of [3H]pirenzepine was observed in schizophrenia patients, which suggested a reduction of muscarinic M1 and M4 receptor densities in the STG of schizophrenia patients. A tendency toward decreased [3H]AF-DX384 binding density (34%, P = 0.09) was also observed in schizophrenia patients compared with controls. Because of the positive correlation between [3H]pirenzepine and [3H]AF-DX384 binding, and, insofar as both ligands have high affinities for the M4 receptor, the involvement of M4 receptor alteration is also suggested in the STG in schizophrenia. These results suggest that changes of the muscarinic receptors M1 and M4 might contribute to the STG pathology in schizophrenia. © 2005 Wiley-Liss, Inc. [source] Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic functionAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2006R. M. Eglen Summary 1 Muscarinic M1,M5 receptors mediate the metabotropic actions of acetylcholine in the nervous system. A growing body of data indicate they also mediate autocrine functions of the molecule. The availability of novel and selective muscarinic agonists and antagonists, as well as in vivo gene disruption techniques, has clarified the roles of muscarinic receptors in mediating both functions of acetylcholine. 2 Selective M1 agonists or mixed M1 agonists/M2 antagonists may provide an approach to the treatment of cognitive disorders, while M3 antagonism, or mixed M2/M3 antagonists, are approved for the treatment of contractility disorders including overactive bladder and chronic obstructive pulmonary disease. Preclinical data suggest that selective agonism of the M4 receptor will provide novel anti-nociceptive agents, while therapeutics-based upon agonism or antagonism of the muscarinic M5 receptor have yet to be reported. 3 The autocrine functions of muscarinic receptors broadly fall into two areas , control of cell growth or proliferation and mediation of the release of chemical mediators from epithelial cells, ultimately causing muscle relaxation. The former particularly are involved in embryological development, oncogenesis, keratinocyte function and immune responsiveness. The latter regulate contractility of smooth muscle in the vasculature, airways and urinary bladder. 4 Most attention has focused on muscarinic M1 or M3 receptors which mediate lymphocyte immunoresponsiveness, cell migration and release of smooth muscle relaxant factors. Muscarinic M4 receptors are implicated in the regulation of keratinocyte adhesion and M2 receptors in stem cell proliferation and development. Little data are available concerning the M5 receptor, partly due to the difficulties in defining the subtype pharmacologically. 5 The autocrine functions of acetylcholine, like those in the nervous system, involve activation of several muscarinic receptor subtypes. Consequently, the role of these subtypes in autocrine, as well neuronal cholinergic systems, significantly expands their importance in physiology and pathophysiology. [source] | ||||||||||