Transient receptor potential canonical 1 (TRPC1) protein is abundantly expressed in cardiomyocytes. While TRPC1 is supposed to be critically involved in cardiac hypertrophy, its physiological role in cardiomyocytes is poorly understood. We investigated the subcellular location of TRPC1 and its contribution to Ca signaling in mammalian ventricular myocytes. Immunolabeling, three-dimensional scanning confocal microscopy and quantitative colocalization analysis revealed an abundant intracellular location of TRPC1 in neonatal rat ventricular myocytes (NRVMs) and adult rabbit ventricular myocytes. TRPC1 was colocalized with intracellular proteins including sarco/endoplasmic reticulum Ca ATPase 2 in the sarcoplasmic reticulum (SR). Colocalization with wheat germ agglutinin, which labels the glycocalyx and thus marks the sarcolemma including the transverse tubular system, was low. Super-resolution and immunoelectron microscopy supported the intracellular location of TRPC1. We investigated Ca signaling in NRVMs after adenoviral TRPC1 overexpression or silencing. In NRVMs bathed in Na and Ca free solution, TRPC1 overexpression and silencing was associated with a decreased and increased SR Ca content, respectively. In isolated rabbit cardiomyocytes bathed in Na and Ca free solution, we found an increased decay of the cytosolic Ca concentration [Ca] and increased SR Ca content in the presence of the TRPC channel blocker SKF-96365. In a computational model of rabbit ventricular myocytes at physiological pacing rates, Ca leak through SR TRPC channels increased the systolic and diastolic [Ca] with only minor effects on the action potential and SR Ca content. Our studies suggest that TRPC1 channels are localized in the SR, and not present in the sarcolemma of ventricular myocytes. The studies provide evidence for a role of TRPC1 as a contributor to SR Ca leak in cardiomyocytes, which was previously explained by ryanodine receptors only. We propose that the findings will guide us to an understanding of TRPC1 channels as modulators of [Ca] and contractility in cardiomyocytes.
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| http://dx.doi.org/10.1016/j.yjmcc.2020.01.008 | DOI Listing |
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