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 4alpha is critical for its contribution to cardiomyocyte hypertrophy.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Cooley, N., Grubb, D. R., Luo, J., Woodcock, E. A.,
["Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.", "Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.", "Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.", "Molecular Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia liz.woodcock@bakeridi.edu.au."]
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 PLCbeta1b that is scaffolded onto a SH3 and ankyrin repeat protein 3 (Shank3) complex at the sarcolemma. TrpC4 exists as two splice variants (TrpC4alpha and TrpC4beta) that differ only in an 84-residue sequence that binds to phosphatidylinositol(4,5)bisphosphate (PIP2), the substrate of PLCbeta1b. In neonatal rat cardiomyocytes, TrpC4alpha, but not TrpC4beta, coimmunoprecipitated with both PLCbeta1b and Shank3. Heightened PLCbeta1b expression caused TrpC4alpha, but not TrpC4beta, translocation to the sarcolemma, where it colocalized with PLCbeta1b. When overexpressed in cardiomyocytes, TrpC4alpha, but not TrpC4beta, 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 PLCbeta1b, or PLCbeta1b-coupled receptor activation, by 72 +/- 8% and 39 +/- 5 %, respectively. We conclude that TrpC4alpha is selectively involved in mechanisms downstream of PLCbeta1b culminating in cardiomyocyte hypertrophy, and that the hypertrophic response is dependent on the TrpC4alpha splice variant-specific sequence that binds to PIP2.
PMID: 25049082External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Screening Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vitro validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vivo validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Characterization Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Functional consequence Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b top
Screening Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Experimental screening Non-experimental screening Reference
TRP channel construct Interactor source
TRP channel Interactor Method Species Region Species Organ/tissue Sample type
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 SHANK Inference Prediction 25049082
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Screening Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vitro validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vivo validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Characterization Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Functional consequence Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b top
Validation: In vivo validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with endogenous proteins Assay with overexpressed proteins Reference
Cell or tissue Cell or tissue TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Species Region
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ1 Co-immunoprecipitation Neonatal rat ventricular myocytes Human Full-length Mouse Full-length 25049082
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ1 Co-immunofluorescence staining Neonatal rat ventricular myocytes Not used Mouse Full-length 25049082
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 SHANK Co-immunoprecipitation Neonatal rat ventricular myocytes Human Full-length Not used 25049082
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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