TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells.

Transient receptor potential cation channel subfamily M member 4 (TRPM4) is a Ca-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 Ca signaling of PACs using pharmacological tools and TRPM4-deficient mice. We found a significant Ca-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 Ca-dependent depolarization of PACs from a resting membrane potential of -44.4 ± 2.9 to -27.7 ± 3 mV. Furthermore, we showed that Ca influx was higher in the TRPM4 KO- and CBA-treated PACs than in control cells. As hormone-induced repetitive Ca transients partially rely on Ca influx in PACs, the role of TRPM4 was also assessed on Ca oscillations elicited by physiologically relevant concentrations of the cholecystokinin analog cerulein. These data show that the amplitude of Ca 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 Ca. In conclusion, TRPM4 links intracellular Ca signaling to membrane potential as a negative feedback regulator of Ca entry in PACs.