LRRC8 channel complexes counterbalance KATP channels to mediate swell-secretion coupling in mouse pancreatic β cells

Insulin secretion from pancreatic β cells is initiated by membrane potential depolarization, followed by activation of voltage-gated Ca2+ channels to trigger Ca2+-mediated Insulin vesicle fusion with the β cell plasma membrane. Here, we show that β cell swelling associated with glucose metabolism was sensed by LRRC8 channel complexes and contributed to Insulin secretion. Hypertonic perfusate (360-380 mOsm) dose dependently impaired glucose-stimulated Insulin secretion by counteracting β cell swelling. Hypotonic perfusate alone, independent of glucose stimulation or KATP channel closure, was sufficient to increase β cell intracellular Ca2+ and trigger Insulin secretion. Inhibition of sodium-potassium-chloride cotransporter-1 with bumetanide, which diminished the intracellular Cl- concentration in β cells and consequently reduced Cl- efflux via LRRC8 channel complexes, also significantly reduced hypotonic-stimulated Insulin secretion. Finally, stimulation of Insulin secretion by the Glucokinase Activator GKA50, which is known to induce β cell swelling, was entirely suppressed in β cell-targeted Lrrc8a KO islets. These data support a model wherein the LRRC8 channel complex senses β cell swelling triggered by glucose metabolism and regulates β cell Insulin secretion through activation of LRRC8-mediated Cl- efflux.

Beta cells; Cell biology; Insulin; Ion channels; Metabolism.