Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists

Richards, Mary H.; Giersbergen, Paul L. M. van

doi:10.1111/j.1476-5381.1995.tb13339.x

Cited by 57 publications

(51 citation statements)

References 26 publications

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“…McN-A-343 is an agonist that shows functional selectivity for M 1 receptors (Heldman et al, 1996) but displays nonselective affinity for all muscarinic receptors (Richards and van Giersbergen, 1995;Ensinger et al, 1997). In the present study, McN-A-343 produced a partial agonist relaxant response, with higher concentrations producing a frank contraction in tissues from wild-type mice and a return to baseline force in tissues from M 3 receptor knockout mice.…”

Section: Discussionmentioning

confidence: 62%

M₁Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M₃Receptor Knockout Mice

Stengel

Cohen²

2003

J Pharmacol Exp Ther

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Muscarinic receptors can mediate both contractile and relaxant responses in smooth muscle. The stomach fundus from wildtype mice possesses a neuronal M 1 receptor that mediates relaxation to carbamylcholine and (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride but is masked by M 3 receptor-mediated contraction to both agonists. When the M 3 receptor was deleted, cholinergic-induced relaxation was unmasked. M 1 receptor antagonism with pirenzepine, nitric oxide (NO) synthase inhibition with N -nitro-L-arginine methyl ester hydrochloride, and inhibition of neuronal activation with tetrodotoxin abolished relaxation to McN-A-343 in tissues from M 3 receptor knockout mice, supporting the neuronal localization of an M 1 receptor that activated NO release to effect relaxation. However, the cyclooxygenase inhibitor indomethacin did not affect contraction or relaxation to carbamylcholine in stomach fundus from wild-type or M 3 receptor knockout mice, indicating that cyclooxygenase products played no role in these responses. The neuronal M 1 receptor modulated relaxation induced by carbamylcholine and McN-A-343 but not relaxation induced by electric field stimulation of the stomach fundus. These data support the presence of M 1 receptor-mediated relaxation in the stomach and suggest that when the M 3 receptor is eliminated or blocked, M 1 receptor-mediated gastric relaxation may be enhanced, possibly leading to alterations in gastric emptying and subsequent effects on body weight.

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Section: Discussionmentioning

confidence: 62%

M₁Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M₃Receptor Knockout Mice

Stengel

Cohen²

2003

J Pharmacol Exp Ther

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“…The M 1 and the M 2 group are associated with phospholipase C activation and adenylate cyclase inhibition, respectively (18). Oxotremorine is a partial and a full agonist for the M 1 and the M 2 group (32,39,40), respectively, whereas muscarine and oxotremorine-M are full agonists for both (32,40). The present experiment extended the list of partial agonists for the musca- rinic receptor-mediated inhibition of TASK channel activity in rat AM cells.…”

Section: Muscarinic Receptor Subtypes Involved In Task Channel Inhibimentioning

confidence: 80%

“…This notion was supported by the failure of RS-86 to induce an inward current. It was reported that RS-86 has no affinity against the M 5 and is a partial or full agonist for the remaining four muscarinic receptor subtypes (31,32). The analysis of the effect of a muscarinic antagonist also clearly negate the involvement of M 4 .…”

Section: Muscarinic Receptor Subtypes Involved In Task Channel Inhibimentioning

confidence: 95%

“…Pilocarpine and McN-A were not efficient in producing an inward current through TASK channel inhibition, as was noted with oxotremorine (7): the amplitudes of inward currents in response to both of them were less than half the muscarine-induced currents. Pilocarpine was a partial agonist for the M 2 , M 3 , and M 5 receptors and a full agonist for the M 4 receptor (32, 40), whereas McN-A was a partial and a full agonist for the M 5 and the M 4 receptor, respectively (32), and had practically no action on the M 3 -mediated increase in phosphatidyl inositol turnover in cell lines (32). Furthermore, VU70, a M 1 specific agonist, produced marginal inward currents, the amplitudes of which were about 10% of those in response to muscarine.…”

Section: Muscarinic Receptor Subtypes Involved In Task Channel Inhibimentioning

confidence: 99%

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Identification and Role of Muscarinic Receptor Subtypes Expressed in Rat Adrenal Medullary Cells

et al. 2011

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Abstract. The muscarinic receptor is known to be involved in the acetylcholine (ACh)-induced secretion of catecholamines in the adrenal medullary (AM) cells of various mammals. The muscarinic receptor subtype involved and its physiological role, however, have not been elucidated yet. Thus, we investigated these issues in acutely isolated rat AM cells and perfused rat adrenal medulla. The RT-PCR analysis revealed the presence of M 2 , M 3 , M 4 , and M 5 mRNAs. Immunocytochemistry with specific antibodies showed that M 5 -like immunoreactivities (IRs) were detected at half the cell membrane area, which was much larger than that with M 3 -or M 4 -like IRs. Muscarine produced inward currents in a dose-dependent manner. Pilocarpine, McN-A-343, and oxotremorine were less efficient than muscarine; and RS-86, which has no action on the M 5 receptor, produced no current. Electrical stimulation of nerve fibers produced a frequency-dependent increase in the Ca 2+ signal in perfused adrenal medullae. Muscarinic receptors were found to be involved in neuronal transmission in AM cells in the presence of a cholinesterase inhibitor, which suppresses ACh degradation. We concluded that the M 5 receptor is the major muscarinic receptor subtype in rat AM cells and may be involved in neuronal transmission under conditions where ACh spills over the synapse.

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“…Although the degree of M 4 selectivity displayed by these agents is relatively modest, the two CMI compounds nevertheless are important novel pharmacological tools. It should be noted in this context that another muscarinic agonist, McN-A-343, has also been reported to exhibit a certain degree of M 4 receptor selectivity (Lazareno et al, 1993;Richards and van Giersbergen, 1995).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Muscarinic Agonist-Induced Analgesia in Muscarinic Acetylcholine Receptor Knockout Mice

Duttaroy

Gomeza²,

Gan³

et al. 2002

Mol Pharmacol

136

131

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Centrally active muscarinic agonists display pronounced analgesic effects. Identification of the specific muscarinic acetylcholine receptor (mAChR) subtype(s) mediating this activity is of considerable therapeutic interest. To examine the roles of the M 2 and M 4 receptor subtypes, the two G i /G o -coupled mAChRs, in mediating agonist-dependent antinociception, we generated a mutant mouse line deficient in both M 2 and M 4 mAChRs [M 2 /M 4 double-knockout (KO) mice]. In wild-type mice, systemic, intrathecal, or intracerebroventricular administration of centrally active muscarinic agonists resulted in robust analgesic effects, indicating that muscarinic analgesia can be mediated by both spinal and supraspinal mechanisms. Strikingly, muscarinic agonist-induced antinociception was totally abolished in M 2 /M 4 double-KO mice, independent of the route of application. The nonselective muscarinic agonist oxotremorine showed reduced analgesic potency in M 2 receptor single-KO mice, but retained full analgesic activity in M 4 receptor single-KO mice. In contrast, two novel muscarinic agonists chemically derived from epibatidine, CMI-936 and CMI-1145, displayed reduced analgesic activity in both M 2 and M 4 receptor single-KO mice, independent of the route of application. Radioligand binding studies indicated that the two CMI compounds, in contrast to oxotremorine, showed Ͼ6-fold higher affinity for M 4 than for M 2 receptors, providing a molecular basis for the observed differences in agonist activity profiles. These data provide unambiguous evidence that muscarinic analgesia is exclusively mediated by a combination of M 2 and M 4 mAChRs at both spinal and supraspinal sites. These findings should be of considerable relevance for the development of receptor subtype-selective muscarinic agonists as novel analgesic drugs.

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Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists

Cited by 57 publications

References 26 publications

M₁Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M₃Receptor Knockout Mice

M₁Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M₃Receptor Knockout Mice

Identification and Role of Muscarinic Receptor Subtypes Expressed in Rat Adrenal Medullary Cells

Evaluation of Muscarinic Agonist-Induced Analgesia in Muscarinic Acetylcholine Receptor Knockout Mice

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Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists

Cited by 57 publications

References 26 publications

M1Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M3Receptor Knockout Mice

M1Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M3Receptor Knockout Mice

Identification and Role of Muscarinic Receptor Subtypes Expressed in Rat Adrenal Medullary Cells

Evaluation of Muscarinic Agonist-Induced Analgesia in Muscarinic Acetylcholine Receptor Knockout Mice

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M₁Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M₃Receptor Knockout Mice

M₁Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M₃Receptor Knockout Mice