INDUCTION OF THE CHOLESTEROL METABOLIC PATHWAY REGULATES THE FARNESYLATION OF RAS IN EMBRYONIC CHICK HEART-CELLS - A NEW ROLE FOR RAS IN REGULATING THE EXPRESSION OF MUSCARINIC RECEPTORS AND G-PROTEINS

We propose a novel mechanism for the regulation of the processing of R as and demonstrate a new function for Ras in regulating the expression of cardiac autonomic receptors and their associated G proteins, We ha ve demonstrated previously that induction of endogenous cholesterol sy nthesis in cultured cardiac myocytes resulted in a coordinated increas e in expression of muscarinic receptors, the G protein alpha-subunit, G-alpha(i2), and the inward rectifying K+ channel, GIRK1, These change s in gene expression were associated with a marked increase in the res ponse of heart cells to parasympathetic stimulation, In this study, we demonstrate that the induction of the cholesterol metabolic pathway r egulates Ras processing and that Ras regulates expression of G-alpha(i 2), We show that in primary cultured myocytes most of the RAS is local ized to the cytoplasm in an unfarnesylated form, Induction of the chol esterol metabolic pathway results in increased farnesylation and membr ane association of RAS, Studies of Ras mutants expressed in cultured h eart cells demonstrate that activation of Ras by induction of the chol esterol metabolic pathway results in increased expression of G-alpha(i 2) mRNA, Hence farnesylation of Ras is a regulatable process that play s a novel role in the control of second messenger pathways.