Gq-initiated cardiomyocyte hypertrophy is mediated by phospholipase Cbeta1b.
Activation of the heterotrimeric G protein Gq causes cardiomyocyte hypertrophy in vivo and in cell culture models. Hypertrophic responses induced by pressure or volume overload are exacerbated by increased Gq activity and ameliorated by Gq inhibition. Gq activates phospholipase Cbeta (PLCbeta) subtypes, resulting in generation of the intracellular messengers inositol(1,4,5)tris-phosphate [Ins(1,4,5)P(3)] and sn-1,2-diacylglycerol (DAG), which regulate intracellular Ca(2+) and conventional protein kinase C subtypes, respectively. Gq can also signal independently of PLCbeta, and the involvement of either Ins(1,4,5)P(3) or DAG in cardiomyocyte hypertrophy has not been unequivocally established. Overexpression of one splice variant of PLCbeta1, specifically PLCbeta1b, in neonatal rat cardiomyocytes causes increased cell size, elevated protein/DNA ratio, and heightened expression of the hypertrophy-related marker gene, atrial natriuretic peptide. The other splice variant, PLCbeta1a, had no effect. Expression of a 32-aa C-terminal PLCbeta1b peptide, which competes with PLCbeta1b for sarcolemmal association, prevented PLC activation and eliminated hypertrophic responses initiated by Gq or Gq-coupled alpha(1)-adrenergic receptors. In contrast, a PLCbeta1a C-terminal peptide altered neither PLC activity nor cellular hypertrophy. We conclude that hypertrophic responses initiated by Gq are mediated specifically by PLCbeta1b. Preventing PLCbeta1b association with the sarcolemma may provide a useful therapeutic target to limit hypertrophy.
Filtz
Theresa M
TM
Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St. Kilda Rd. Central, Melbourne 8008, VIC, Australia.
Grubb
David R
DR
McLeod-Dryden
Tiffany J
TJ
Luo
Jieting
J
Woodcock
Elizabeth A
EA
D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000096:biosynthesis* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D054799:Phospholipase C beta / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis*
D058646:Adrenergic alpha-1 Receptor Agonists; D018340:Receptors, Adrenergic, alpha-1; D054799:Phospholipase C beta; C518035:Plcb1 protein, rat; D043802:GTP-Binding Protein alpha Subunits, Gq-G11