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Mol Pharmacol. 2014 Oct;86(4):399-405. doi: 10.1124/mol.114.093690. Epub 2014 Jul 21.

The phosphatidylinositol(4,5)bisphosphate-binding sequence of transient receptor potential channel canonical 4α is critical for its contribution to cardiomyocyte hypertrophy.

Author information

1
Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
2
Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia liz.woodcock@bakeridi.edu.au.

Abstract

Cardiomyocyte hypertrophy requires a source of Ca(2+) distinct from the Ca(2+) that regulates contraction. The canonical transient receptor potential channel (TrpC) family, a family of cation channels regulated by activation of phospholipase C (PLC), has been implicated in this response. Cardiomyocyte hypertrophy downstream of Gq-coupled receptors is mediated specifically by PLCβ1b that is scaffolded onto a SH3 and ankyrin repeat protein 3 (Shank3) complex at the sarcolemma. TrpC4 exists as two splice variants (TrpC4α and TrpC4β) that differ only in an 84-residue sequence that binds to phosphatidylinositol(4,5)bisphosphate (PIP2), the substrate of PLCβ1b. In neonatal rat cardiomyocytes, TrpC4α, but not TrpC4β, coimmunoprecipitated with both PLCβ1b and Shank3. Heightened PLCβ1b expression caused TrpC4α, but not TrpC4β, translocation to the sarcolemma, where it colocalized with PLCβ1b. When overexpressed in cardiomyocytes, TrpC4α, but not TrpC4β, increased cell area (893 ± 18 to 1497 ± 29 mm(2), P < 0.01) and marker gene expression (atrial natriuretic peptide increased by 409 ± 32%, and modulatory calcineurin inhibitory protein 1 by 315 ± 28%, P < 0.01). Dominant-negative TrpC4 reduced hypertrophy initiated by PLCβ1b, or PLCβ1b-coupled receptor activation, by 72 ± 8% and 39 ± 5 %, respectively. We conclude that TrpC4α is selectively involved in mechanisms downstream of PLCβ1b culminating in cardiomyocyte hypertrophy, and that the hypertrophic response is dependent on the TrpC4α splice variant-specific sequence that binds to PIP2.

PMID:
25049082
DOI:
10.1124/mol.114.093690
[Indexed for MEDLINE]

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