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Volume 270, Number 15, Issue of April 14, pp. 8446-8451, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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MMuscarinic Receptors Heterologously Expressed in Cardiac Myocytes Mediate Ras-dependent Changes in Gene Expression

M. Teresa Ramirez , Ginell R. Post , Prakash V. Sulakhe , Joan Heller Brown

Stimulation of -adrenergic receptors in neonatal ventricular cardiomyocytes induces hypertrophic changes including activation of the atrial natriuretic factor (ANF) gene. This receptor couples to Gto activate phospholipase C (PLC) and protein kinase C, which have been implicated as mediators of the hypertrophic response. To directly determine whether receptor coupling to G/PLC is sufficient to induce ANF expression, we expressed wild-type and chimeric muscarinic cholinergic receptors (mAChRs) with altered G-protein coupling properties in cardiac myocytes and examined their ability to activate an ANF promoter/luciferase reporter gene. The cholinergic agonist carbachol failed to induce transcriptional activation of the ANF reporter gene through endogenous G-linked MmAChRs or in cells transfected with MmAChRs. In contrast, in cells transfected with MmAChRs, which effectively couple to G/PLC, carbachol increased ANF reporter gene expression 10-fold and also increased ANF protein, as determined by immunofluorescence. Carbachol-mediated ANF gene expression was inhibited by the mAChR antagonist pirenzepine with a Kvalue characteristic of an MmAChR. Studies using chimeric M- and MmAChRs demonstrated that the N-terminal 21 amino acids of the third intracellular loop of the MmAChR were required for receptor coupling to ANF gene expression. This region, previously shown to specify receptor coupling to G/PLC, also conferred partial activity to a chimeric Mreceptor. We further demonstrated that MmAChR coupling to ANF gene expression was Ras-dependent since co-expression of dominant-interfering Ala-15 Ras inhibited MmAChR-induced ANF expression by 60%. In contrast, ANF expression induced by the chimeric Mreceptor was not blocked by dominant-interfering Ras. We suggest that receptor coupling to G/PLC is sufficient to induce ANF expression and that a Ras-dependent pathway contributes additional signals required for maximal MmAChR-mediated ANF gene expression.

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