Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):7000-5. doi: 10.1073/pnas.1001825107. Epub 2010 Mar 29.

TRPC channels are necessary mediators of pathologic cardiac hypertrophy.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Wu, X., Eder, P., Chang, B., Molkentin, J. D.,
["Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA."]
Pathologic hypertrophy of the heart is regulated through membrane-bound receptors and intracellular signaling pathways that function, in part, by altering Ca(2+) handling and Ca(2+)-dependent signaling effectors. Transient receptor potential canonical (TRPC) channels are important mediators of Ca(2+)-dependent signal transduction that can sense stretch or activation of membrane-bound receptors. Here we generated cardiac-specific transgenic mice that express dominant-negative (dn) TRPC3, dnTRPC6, or dnTRPC4 toward blocking the activity of the TRPC3/6/7 or TRPC1/4/5 subfamily of channels in the heart. Remarkably, all three dn transgenic strategies attenuated the cardiac hypertrophic response following either neuroendocrine agonist infusion or pressure-overload stimulation. dnTRPC transgenic mice also were partially protected from loss of cardiac functional performance following long-term pressure-overload stimulation. Importantly, adult myocytes isolated from hypertrophic WT hearts showed a unique Ca(2+) influx activity under store-depleted conditions that was not observed in myocytes from hypertrophied dnTRPC3, dnTRPC6, or dnTRPC4 hearts. Moreover, dnTRPC4 inhibited the activity of the TRPC3/6/7 subfamily in the heart, suggesting that these two subfamilies function in coordinated complexes. Mechanistically, inhibition of TRPC channels in transgenic mice or in cultured neonatal myocytes significantly reduced activity in the calcineurin-nuclear factor of activated T cells (NFAT), a known Ca(2+)-dependent hypertrophy-inducing pathway. Thus, TRPC channels are necessary mediators of pathologic cardiac hypertrophy, in part through a calcineurin-NFAT signaling pathway.
PMID: 20351294External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
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
TRPC3 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 NCX1 Co-immunofluorescence staining dnTRPC3 TG mouse heart myocyte 20351294
TRPC3 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPC4 Co-immunoprecipitation TRPC3 dnTRPC4 DTG mouse heart lysataes 20351294
TRPC3 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPC6 Co-immunoprecipitation dnTRPC6 Neonatal rat ventricular myocytes 20351294
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPC3 Co-immunoprecipitation TRPC3 dnTRPC4 DTG mouse heart lysataes 20351294
TRPC6 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPC3 Co-immunoprecipitation dnTRPC6 Neonatal rat ventricular myocytes 20351294
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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