TRPM4 controls insulin secretion in pancreatic -cells

TRPM4 is a calcium-activated non-selective cation channel that is widely expressed and proposed to be involved in cell depolarization. n excitable cells, TRPM4 may regulate calcium influx by causing the depolarization that drives the activation of voltage-dependent calcium hannels. We here report that insulin-secreting cells of the rat pancreatic -cell line INS-1 natively express TRPM4 proteins and generate arge depolarizing membrane currents in response to increased intracellular calcium. These currents exhibit the characteristics of TRPM4 nd can be suppressed by expressing a dominant negative TRPM4 construct, resulting in significantly decreased insulin secretion in response o a glucose stimulus. Reduced insulin secretion was also observed with arginine vasopressin stimulation, a Gq-coupled receptor agonist in -cells. Moreover, the recruitment of TRPM4 currents was biphasic in both INS-1 cells as well as HEK-293 cells overexpressing TRPM4. he first phase is due to activation of TRPM4 channels localized within the plasma membrane followed by a slower secondary phase, which s caused by the recruitment of TRPM4-containing vesicles to the plasma membrane during exocytosis. The secondary phase can be observed uring perfusion of cells with increasing [Ca]i, replicated with agonist stimulation, and coincides with an increase in cell capacitance, loss f FM1-43 dye, and vesicle fusion. Our data suggest that TRPM4 may play a key role in the control of membrane potential and electrical ctivity of electrically excitable secretory cells and the dynamic translocation of TRPM4 from a vesicular pool to the plasma membrane via a2+-dependent exocytosis may represent a key shortand midterm regulatory mechanism by which cells regulate electrical activity. 2006 Elsevier Ltd. All rights reserved.