RT Journal Article SR Electronic T1 The PIP2-binding Sequence of Transient Receptor Potential Channel Canonical 4α is Critical for its Contribution to Cardiomyocyte Hypertrophy JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.114.093690 DO 10.1124/mol.114.093690 A1 Nicola Cooley A1 David R Grubb A1 Jieting Luo A1 Elizabeth A Woodcock YR 2014 UL http://molpharm.aspetjournals.org/content/early/2014/07/21/mol.114.093690.abstract AB Cardiomyocyte hypertrophy requires a source of Ca2+ distinct from the Ca2+ that regulates contraction. The canonical transient receptor potential channel family (TrpC), 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 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, co-immunoprecipitated with both PLCβ1b and Shank3. Heightened PLCβ1b expression caused TrpC4α, but not TrpC4β translocation to the sarcolemma where it co-localized with PLCβ1b. When overexpressed in cardiomyocytes, TrpC4α but not TrpC4β, increased cell area (893±18 to 1497±29 mm2, 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.