Coupling of subtypes of the muscarinic receptor to adenylate cyclase in the corpus striatum and heart

F. J. Ehlert, F. M. Delen, S. H. Yun, D. J. Friedman, D. W. Self

Research output: Contribution to journalArticle

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Abstract

The binding properties of a series of muscarinic antagonists were compared with their ability to antagonize muscarinic receptor-mediated inhibition of adenylate cyclase activity in homogenates of the corpus striatum and heart of rats. When measured by the competitive inhibition of the binding of the muscarinic antagonist N-[3H]methylscopolamine, the binding properties of selective muscarinic antagonists in the corpus striatum and cerebral cortex were consistent with a model incorporating a minimum of three populations of muscarinic receptors, a high affinity site for pirenzepine (M1), a high affinity site for AF-DX 116 {11[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one} (M2) and a third population (non-M1, non-M2 sites) displaying low affinity for the latter antagonists. The results of similar experiments on the heart showed that this tissue contained a uniform population of M2 muscarinic receptors. The binding properties of the M2 receptor in cerebral cortex and corpus striatum were also investigated directly in antagonist-[3H]AF-DX 116 competition experiments and, although the high affinity AF-DX 116 site in brain (M2) exhibited selectivity for the cardioselective antagonists AF-DX 116 and gallamine, some differences were noted between M2 sites in brain and heart. The muscarinic adenylate cyclase response in the corpus striatum was relatively insensitive to the M2 selective antagonists AF-DX 116 and gallamine as well as the M1 selective antagonist pirenzepine, suggesting that non-M1, non-M2 sites inhibit adenylate cyclase activity in the corpus striatum. In contrast, the effects of muscarinic antagonists on the muscarinic adenylate cyclase response in the heart were consistent with the postulate that M2 receptors inhibit adenylate cyclase activity in this tissue.

Original languageEnglish (US)
Pages (from-to)660-671
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume251
Issue number2
StatePublished - 1989

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Corpus Striatum
Muscarinic Receptors
Adenylyl Cyclases
Muscarinic Antagonists
Gallamine Triethiodide
Pirenzepine
Cerebral Cortex
Cholinergic Agents
N-Methylscopolamine
Muscarinic M2 Receptors
Population
Competitive Binding
Brain
otenzepad

ASJC Scopus subject areas

  • Pharmacology

Cite this

Coupling of subtypes of the muscarinic receptor to adenylate cyclase in the corpus striatum and heart. / Ehlert, F. J.; Delen, F. M.; Yun, S. H.; Friedman, D. J.; Self, D. W.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 251, No. 2, 1989, p. 660-671.

Research output: Contribution to journalArticle

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abstract = "The binding properties of a series of muscarinic antagonists were compared with their ability to antagonize muscarinic receptor-mediated inhibition of adenylate cyclase activity in homogenates of the corpus striatum and heart of rats. When measured by the competitive inhibition of the binding of the muscarinic antagonist N-[3H]methylscopolamine, the binding properties of selective muscarinic antagonists in the corpus striatum and cerebral cortex were consistent with a model incorporating a minimum of three populations of muscarinic receptors, a high affinity site for pirenzepine (M1), a high affinity site for AF-DX 116 {11[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one} (M2) and a third population (non-M1, non-M2 sites) displaying low affinity for the latter antagonists. The results of similar experiments on the heart showed that this tissue contained a uniform population of M2 muscarinic receptors. The binding properties of the M2 receptor in cerebral cortex and corpus striatum were also investigated directly in antagonist-[3H]AF-DX 116 competition experiments and, although the high affinity AF-DX 116 site in brain (M2) exhibited selectivity for the cardioselective antagonists AF-DX 116 and gallamine, some differences were noted between M2 sites in brain and heart. The muscarinic adenylate cyclase response in the corpus striatum was relatively insensitive to the M2 selective antagonists AF-DX 116 and gallamine as well as the M1 selective antagonist pirenzepine, suggesting that non-M1, non-M2 sites inhibit adenylate cyclase activity in the corpus striatum. In contrast, the effects of muscarinic antagonists on the muscarinic adenylate cyclase response in the heart were consistent with the postulate that M2 receptors inhibit adenylate cyclase activity in this tissue.",
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