TRPC1 channels underlie stretch-modulated sarcoplasmic reticulum calcium leak in cardiomyocytes

Abstract

Transient receptor potential canonical 1 (TRPC1) channels are Ca2+-permeable ion channels expressed in cardiomyocytes. An involvement of TRPC1 channels in cardiac diseases is widely established. However, the physiological role of TRPC1 channels and the mechanisms through which they contribute to disease development are still under investigation. Our prior work suggested that TRPC1 forms Ca2+ leak channels located in the sarcoplasmic reticulum (SR) membrane. Prior studies suggested that TRPC1 channels in the cell membrane are mechanosensitive, but this was not yet investigated in cardiomyocytes or for SR localized TRPC1 channels. We applied adenoviral transfection to overexpress or suppress TRPC1 expression in neonatal rat ventricular myocytes (NRVMs). Transfections were evaluated with RT-qPCR, western blot, and fluorescent imaging. Single-molecule localization microscopy revealed high colocalization of exogenously expressed TRPC1 and the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2). To test our hypothesis that TRPC1 channels contribute to mechanosensitive Ca2+ SR leak, we directly measured SR Ca2+ concentration ([Ca2+]SR) using adenoviral transfection with a novel ratiometric genetically encoded SR-targeting Ca2+ sensor. We performed fluorescence imaging to quantitatively assess [Ca2+]SR and leak through TRPC1 channels of NRVMs cultured on stretchable silicone membranes. [Ca2+]SR was increased in cells with suppressed TRPC1 expression vs. control and Transient receptor potential canonical 1-overexpressing cells. We also detected a significant reduction in [Ca2+]SR in cells with Transient receptor potential canonical 1 overexpression when 10% uniaxial stretch was applied. These findings indicate that TRPC1 channels underlie the mechanosensitive modulation of [Ca2+]SR. Our findings are critical for understanding the physiological role of TRPC1 channels and support the development of pharmacological therapies for cardiac diseases.

Mechanosensitive enteric neurons in the guinea pig gastric fundus and antrum

“…After revealing the presence of MEN in all parts of the stomach, we focused on receptors involved in mechanotransduction. The TRPC1 has been shown to be stretch‐activated in spinal neuronal axons, retina, and TRPC1‐expressing oocytes as well as cardiomyocytes 41–44 . This receptor is of interest because it is widely distributed in the MP of the guinea pig small intestine in both cholinergic and nitrergic neurons 26 .…”

“…The TRPC1 has been shown to be stretch-activated in spinal neuronal axons, retina, and TRPC1-expressing oocytes as well as cardiomyocytes. [41][42][43][44] This receptor is of interest because it is widely distributed in the MP of the guinea pig small intestine in both cholinergic and nitrergic neurons. 26 The TRPC antagonist SKF96365 45 led to a significant decrease in the responsiveness of MEN in both the fundus and the antrum, indicating that the TRPC1 might function as a neuronal mechanoreceptor in both regions.…”

Impacto del entrenamiento aeróbico sobre las alteraciones mitocondriales en un modelo de hipertrofia cardiaca patológica: rol de IGF-1 y apelina

“…Crecimiento longitudinal de los cardiomiocitos Hipertrofia excéntrica del Ca 2+ intracelular por el influjo de este ion a favor de su gradiente electroquímico 19,20 . Por otro lado, también estimula el aumento de Ang-II y ET-1 que conlleva a la activación de sus receptores acoplados a proteínas Gq, con el consecuente aumento de la actividad de fosfolipasa C (PLC) e inositol trifosfato (IP3), lo que, a través de varios pasos, también contribuye al aumento del Ca 2+ intracelular 21 .…”