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Molecular Pharmacology

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Research ArticleArticle

The Phosphatidylinositol(4,5)Bisphosphate–Binding Sequence of Transient Receptor Potential Channel Canonical 4α Is Critical for Its Contribution to Cardiomyocyte Hypertrophy

Nicola Cooley, David R. Grubb, Jieting Luo and Elizabeth A. Woodcock
Molecular Pharmacology October 2014, 86 (4) 399-405; DOI: https://doi.org/10.1124/mol.114.093690
Nicola Cooley
Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
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David R. Grubb
Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
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Jieting Luo
Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
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Elizabeth A. Woodcock
Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
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Abstract

Cardiomyocyte hypertrophy requires a source of Ca2+ distinct from the Ca2+ 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 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.

Footnotes

    • Received May 12, 2014.
    • Accepted July 21, 2014.
  • This work was supported by the Australian National Health and Medical Research Council [Grants 1002328, 10007712, and 1022678]; the Victorian Government’s Operational Infrastructure Support Program; and a Baker IDI Heart and Diabetes Institute commercialization grant. E.A.W. is a fellow of the Australian National Health and Medical Research Council [Grant 586621].

  • dx.doi.org/10.1124/mol.114.093690.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (4)
Molecular Pharmacology
Vol. 86, Issue 4
1 Oct 2014
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Research ArticleArticle

TrpC4α Promotes Hypertrophy

Nicola Cooley, David R. Grubb, Jieting Luo and Elizabeth A. Woodcock
Molecular Pharmacology October 1, 2014, 86 (4) 399-405; DOI: https://doi.org/10.1124/mol.114.093690

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Research ArticleArticle

TrpC4α Promotes Hypertrophy

Nicola Cooley, David R. Grubb, Jieting Luo and Elizabeth A. Woodcock
Molecular Pharmacology October 1, 2014, 86 (4) 399-405; DOI: https://doi.org/10.1124/mol.114.093690
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