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.
AuthorsDavid R Grubb, Jieting Luo, Yen Lin Yu, Elizabeth A Woodcock
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 26 Issue 2 Pg. 596-603 (Feb 2012) ISSN: 1530-6860 [Electronic] United States
PMID22012123 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Homer protein
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Shank3 protein, rat
  • Phospholipase C beta
  • Plcb1 protein, rat
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Adaptor Proteins, Signal Transducing (antagonists & inhibitors, genetics, metabolism)
  • Animals
  • Animals, Newborn
  • Base Sequence
  • Calcium Signaling
  • Carrier Proteins (genetics, metabolism)
  • Cell Enlargement
  • GTP-Binding Protein alpha Subunits, Gq-G11 (metabolism)
  • Gene Knockdown Techniques
  • In Vitro Techniques
  • Models, Cardiovascular
  • Multiprotein Complexes (metabolism)
  • Myocytes, Cardiac (metabolism, pathology)
  • Nerve Tissue Proteins
  • Phospholipase C beta (metabolism)
  • RNA, Messenger (genetics, metabolism)
  • RNA, Small Interfering (genetics)
  • Rats
  • Rats, Sprague-Dawley
  • Sarcolemma (metabolism)
  • Signal Transduction

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password:
Type Validation Code Shown: