Gq-initiated cardiomyocyte hypertrophy is mediated by phospholipase Cβ1b

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 C beta (PLC beta) 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 Ca2+ and conventional protein kinase C subtypes, respectively. Gq can also signal independently of PLC beta, 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 PLC beta 1, specifically PLC beta 1b, 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, PLC beta 1a, had no effect. Expression of a 32-aa C-terminal PLC beta 1b peptide, which competes with PLC beta 1b for sarcolemmal association, prevented PLC activation and eliminated hypertrophic responses initiated by Gq or Gq-coupled alpha(1)-adrenergic receptors. In contrast, a PLC beta(1)a C-terminal peptide altered neither PLC activity nor cellular hypertrophy. We conclude that hypertrophic responses initiated by Gq are mediated specifically by PLC beta 1b. Preventing PLC beta 1b association with the sarcolemma may provide a useful therapeutic target to limit hypertrophy.-Filtz, T. M., Grubb, D. R., McLeod-Dryden, T. J., Luo, J., Woodcock, E. A. Gq-initiated cardiomyocyte hypertrophy is mediated by phospholipase C beta 1b. FASEB J. 23, 3564-3570 (2009). www.fasebj.org