Scaffolding protein Homer 1c mediates hypertrophic responses downstream of Gq in cardiomyocytes

Abstract

Activation of the heterotrimeric G protein, Gq, causes cardiomyocyte hypertrophy in vivo and in cell models. Responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cβ1b (PLCβ1b), because it localizes at the sarcolemma by binding to Shank3, a high-molecular-weight (MW) scaffolding protein. Shank3 can bind to the Homer family of low-MW scaffolding proteins that fine tune Ca(2+) signaling by facilitating crosstalk between Ca(2+) channels at the cell surface with those on intracellular Ca(2+) stores. Activation of α(1)-adrenergic receptors, expression of constitutively active Gαq (GαqQL), or PLCβ1b initiated cardiomyocyte hypertrophy and increased Homer 1c mRNA expression, by 1.6 ± 0.18-, 1.9 ± 0.17-, and 1.5 ± 0.07-fold, respectively (means ± se, 6 independent experiments, P<0.05). Expression of Homer 1c induced an increase in cardiomyocyte area from 853 ± 27 to 1146 ± 31 μm(2) (P<0.05); furthermore, expression of dominant-negative Homer (Homer 1a) reversed the increase in cell size caused by α(1)-adrenergic agonist or PLCβ1b treatment (1503±48 to 996±28 and 1626±48 to 828±31 μm(2), respectively, P<0.05). Homer proteins were localized near the sarcolemma, associated with Shank3 and phospholipase Cβ1b. We conclude that Gq-mediated hypertrophy involves activation of PLCβ1b scaffolded onto a Shank3/Homer complex. Signaling downstream of Homer 1c is necessary and sufficient for Gq-initiated hypertrophy.