Abstract P225: Possible Involvement of Homer-1b/c in Gq-Mediated Hypertrophy in Cardiomyocytes
Receptor activation of Gq causes hypertrophy in cardiomyocytes, via the activation of phospholipase Cβ 1b (PLCβ1b). PLCβ1b, localizes to the cardiac sarcolemma through an interaction with the multi-domain scaffolding molecule Shank-3 (SH3 and multiple ankyrin repeat domains protein 3; Grubb et al., 2011), which is required for PLC activation and for hypertrophic responses. In the CNS, Shank-3 forms higher order oligomeric complexes with three isoforms of Homer protein homolog 1 (Homer-1), Homer-1a, Homer-1b and Homer-1c. Homer-1b and Homer-1c link G-protein coupled receptors, ionotropic receptors, canonical transient receptor potential channel (TrpC) and intracellular calcium store regulators into a signaling complex. Homer-1a acts as a natural dominant negative, in dynamic competition with Homer-1b and Homer-1c. Neonatal rat ventricular myocytes (NRVM) infected with adenovirus expressing either Gαq(Q209L) (constitutively active Gαq), or its immediate down-stream effector, PLCβ1b, increased Homer-1b/c transcription. Incubation with phenylephrine/propranalol (α1-adrenergic agonist, PE/Pro) also increased Homer-1b/c, but not Homer-1a, mRNA. All treatments caused cardiomyocyte hypertrophy. There was no comparable increase in Homer-1b/c mRNA in NRVM expressing PLCβ1a (inactive splice variant) or incubated with fetal calf serum to induce hypertrophy by Gq-independent mechanisms. Homer-1b/c protein induced by PLCβ1b, Gαq or PE/Pro was primarily localized close to the sarcolemma along with Shank3, PLCβ1b and TrpC4. We conclude that Gαq/PLCβ1b-mediated signaling leads to the up-regulation of Homer-1b/c, that co-localizes with a signaling complex close to the sacrolemma. Induction of Homer-1b/c may be critical in facilitating localized Ca2+ signaling and thereby promoting Gq dependent hypertrophy.
- © 2011 by American Heart Association, Inc.