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.
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."]
["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: 25049082

![]() ![]() ![]() ![]() ![]() |
![]() |
Screening
![]() |
||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Experimental screening | Non-experimental screening | Reference | ||||||||
TRP channel construct | Interactor source | |||||||||
TRP channel | Interactor | Method | Species | Region | Species | Organ/tissue | Sample type | |||
TRPC4 |
![]() |
SHANK | Inference | Prediction | 25049082 |
(
:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)

![]() ![]() ![]() ![]() ![]() |
![]() |
Validation: In vivo validation
![]() |
||||||||||
---|---|---|---|---|---|---|---|---|---|---|
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 |
![]() |
PLCƢ1 | Co-immunoprecipitation | Neonatal rat ventricular myocytes | Human | Full-length | Mouse | Full-length | 25049082 | |
TRPC4 |
![]() |
PLCƢ1 | Co-immunofluorescence staining | Neonatal rat ventricular myocytes | Not used | Mouse | Full-length | 25049082 | ||
TRPC4 |
![]() |
SHANK | Co-immunoprecipitation | Neonatal rat ventricular myocytes | Human | Full-length | Not used | 25049082 |
(
:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
