TY - JOUR T1 - The PIP<sub>2</sub>-binding Sequence of Transient Receptor Potential Channel Canonical 4α is Critical for its Contribution to Cardiomyocyte Hypertrophy JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.093690 SP - mol.114.093690 AU - Nicola Cooley AU - David R Grubb AU - Jieting Luo AU - Elizabeth A Woodcock Y1 - 2014/01/01 UR - http://molpharm.aspetjournals.org/content/early/2014/07/21/mol.114.093690.abstract N2 - 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&lt;0.01) and marker gene expression (atrial natriuretic peptide increased by 409±32% and modulatory calcineurin inhibitory protein 1 by 315±28%, p&lt;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. ER -