TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells

Gyula Diszházi,Zsuzsanna É Magyar,Erika Lisztes,Edit Tóth-Molnár,Péter P Nánási,Rudi Vennekens,Balázs I Tóth,János Almássy

doi:10.1016/j.jbc.2021.101015

Gyula Diszházi, Zsuzsanna É Magyar + Show 6 more

Open Access

https://doi.org/10.1016/j.jbc.2021.101015

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Abstract

Transient receptor potential cation channel subfamily M member 4 (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 (PACs), 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 4-chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]benzoic acid (CBA). 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 analog cerulein. These data show that the amplitude of Ca2+ signals was 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.

Highlights

Triggers the exocytosis of digestive enzymes [1,2,3,4]
In our efforts to find new effectors of Ca2+ signaling in pancreatic acinar cell (PAC), we examined whether Ca2+-regulated ion channels from the transient receptor potential family are expressed in PACs and whether they affect Ca2+ signaling
IP3 receptor (IP3R) isoforms showed high and identical expression, whereas ryanodine receptor (RyR) expression was relatively low, with RyR1 being the major isoform. These results are in accordance with previous results showing that all IP3R isoforms are highly expressed and that RyR has only a complementary role in the Ca2+ signaling of PACs [13, 14, 43,44,45]

Summary

Introduction

Triggers the exocytosis of digestive enzymes [1,2,3,4]. During this process, termed stimulus–secretion coupling, changing [Ca2+]i may exhibit various spatiotemporal patterns, depending on the magnitude of secretagogue stimulation, which eventually determines the quality and quantity of secretion. TRPM4 is an [Ca2+]i-activated nonselective cation channel mediating a significant amount of depolarizing current in several cell types [36].

Results

Conclusion