TRPV1 channels regulate the automaticity of embryonic stem cell‐derived cardiomyocytes through stimulating the Na⁺/Ca²⁺ exchanger current

Abstract

Calcium controls the excitation–contraction coupling in cardiomyocytes. Embryonic stem cell‐derived cardiomyocytes (ESC‐CMs) are an important cardiomyocyte source for regenerative medicine and drug screening. Transient receptor potential vanilloid 1 (TRPV1) channels are nonselective cation channels that permeate sodium and calcium. This study aimed to investigate whether TRPV1 channels regulate the electrophysiological characteristics of ESC‐CMs. If yes, what is the mechanism behind? By immunostaining and subcellular fractionation, followed by western blotting, TRPV1 was found to locate intracellularly. The staining pattern of TRPV1 was found to largely overlap with that of the sarco/endoplasmic reticulum Ca2+‐ATPase, the sarcoplasmic reticulum (SR) marker. By electrophysiology and calcium imaging, pharmacological blocker of TRPV1 and the molecular tool TRPV1β (which could functionally knockdown TRPV1) were found to decrease the rate and diastolic depolarization slope of spontaneous action potentials, and the amplitude and frequency of global calcium transients. By calcium imaging, in the absence of external calcium, TRPV1‐specific opener increased intracellular calcium; this increase was abolished by preincubation with caffeine, which could deplete SR calcium store. The results suggest that TRPV1 controls calcium release from the SR. By electrophysiology, TRPV1 blockade and functional knockdown of TRPV1 decreased the Na+/Ca2+ exchanger (NCX) currents from both the forward and reverse modes, suggesting that sodium and calcium through TRPV1 stimulate the NCX activity. Our novel findings suggest that TRPV1 activity is important for regulating the spontaneous activity of ESC‐CMs and reveal a novel interplay between TRPV1 and NCX in regulating the physiological functions of ESC‐CMs.

Role of Known Transient Receptor Potential Vanilloid Channels in Modulating Cardiac Mechanobiology

“…Antagonism of TRPV1 resulted in reduced expression of cardiomyocyte marker genes ( Qi et al, 2015 ). In a similar model, Zhao et al confirmed the role of TRPV1 in Ca 2+ handling and a potential interaction with the Na + /Ca 2+ exchanger ( Zhao et al, 2021 ). These studies propose that TRPV1 may play a significant role in the Ca 2+ handling in cardiogenesis and in early stage function.…”

Ca2+-Permeable Channels/Ca2+ Signaling in the Regulation of Ileal Na+/Gln Co-Transport in Mice

“…Although TRPV channels in GI sensory neurons have been studied extensively ( De Petrocellis et al, 2012 ; Maurino et al, 2020 ; Grover et al, 2021 ), our study is the first to demonstrate the involvement of Ca 2+ entry via TRPV channels in the regulation of ileal Gln transport in IEC. Na + /Ca 2+ influx mediated by TRPV channels could activate bidirectional ion exchange (NCX), whose transport direction depends on Na + and Ca 2+ gradients and membrane potentials ( Zhang J. et al, 2019 ; Zhao et al, 2021 ). Furthermore, we found that NKA on the serosal side of the intestine are also involved in ileal Gln- I sc , although it is well known that NKA activity is essential to provide potential energy for epithelial ion transports.…”

Mechanical stress concealed force enhancement and ionic transient membrane potential and metabolism in akinesia of stress cardiomyopathy

“…In rodent heart models, angiotensin II induced high left ventricle end-diastolic pressure and end-diastolic pressure-volume relationships [128] . This myocardium passive force-length characteristic brings out contraction zones, and bands are prominent with the dehiscence of myofilaments in adjacent sarcomeres of the diastolic ventricular muscle [129] .…”