Scaffolding protein Homer 1c mediates hypertrophic responses downstream of Gq in cardiomyocytes.
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.
Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne,Victoria, Australia.
David R
DR
Grubb
Jieting
J
Luo
Yen Lin
YL
Yu
Elizabeth A
EA
Woodcock
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049108:Cell Enlargement; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D000072233:Homer Scaffolding Proteins; D066298:In Vitro Techniques; D008955:Models, Cardiovascular; D046912:Multiprotein Complexes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins; D054799:Phospholipase C beta / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C120532:Shank3 protein, rat; D054799:Phospholipase C beta; C518035:Plcb1 protein, rat; D043802:GTP-Binding Protein alpha Subunits, Gq-G11