TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells

Diszházi, Gyula and Magyar, Zsuzsanna Édua and Lisztes, Erika and Tóth-Molnár, Edit and Nánási, Péter Pál and Tóth, Balázs István and Almássy, János (2021) TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells. Journal of Biological Chemistry, 297 (3). ISSN 0021-9258 (print) 1083-351X (online)

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Abstract

TRPM4 is a Ca2+-activated nonselective cation channel that mediates membrane depolarization. Although, a current with the hallmarks of a TRPM4-mediated current has been previously reported in pancreatic acinar cells (PAC), the role of TRPM4 in the regulation of acinar cell function has not yet been explored. In the present study, we identify this TRPM4 current and describe its role in context of Ca2+ signaling of PACs using pharmacological tools and TRPM4-deficient mice. We found a significant Ca2+-activated cation current in PACs that was sensitive to the TRPM4 inhibitors 9-phenanthrol and CBA (4-Chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]benzoic acid). We demonstrated that the CBA-sensitive current was responsible for a Ca2+-dependent depolarization of PACs from a resting membrane potential of -44.4 ± 2.9 to -27.7 ± 3 mV. Furthermore, we showed that Ca2+ influx was higher in the TRPM4 KO- and CBA-treated PACs than in control cells. As hormone induced repetitive Ca2+ transients partially rely on Ca2+ influx in PACs, the role of TRPM4 was also assessed on Ca2+ oscillations elicited by physiologically relevant concentrations of the cholecystokinin analogue cerulein. These data show that the amplitude of Ca2+ signals were significantly higher in TRPM4 KO than in control PACs. Our results suggest that PACs are depolarized by TRPM4 currents to an extent that results in a significant reduction of the inward driving force for Ca2+. In conclusion, TRPM4 links intracellular Ca2+ signaling to membrane potential as a negative feedback regulator of Ca2+ entry in PACs.

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