The neuronal K + Cl − co-transporter 2 ( Slc12a5 ) modulates insulin secretion

Intracellular chloride concentration ([Cl − ] i ) in pancreatic β-cells is kept above electrochemical equilibrium due to the predominant functional presence of Cl − loaders such as the Na + K + 2Cl − co-transporter 1 ( Slc12a2 ) over Cl − extruders of unidentified nature. Using molecular cloning, RT-PCR, Western blotting, immunolocalization and in vitro functional assays, we establish that the “neuron-specific” K + Cl − co-transporter 2 (KCC2, Slc12a5 ) is expressed in several endocrine cells of the pancreatic islet, including glucagon secreting α-cells, but particularly in insulin-secreting β-cells, where we provide evidence for its role in the insulin secretory response. Three KCC2 splice variants were identified: the formerly described KCC2a and KCC2b along with a novel one lacking exon 25 (KCC2a-S25). This new variant is undetectable in brain or spinal cord, the only and most abundant known sources of KCC2. Inhibition of KCC2 activity in clonal MIN6 β-cells increases basal and glucose-stimulated insulin secretion and Ca 2+ uptake in the presence of glibenclamide, an inhibitor of the ATP-dependent potassium (K ATP )-channels, thus suggesting a possible mechanism underlying KCC2-dependent insulin release. We propose that the long-time considered “neuron-specific” KCC2 co-transporter is expressed in pancreatic islet β-cells where it modulates Ca 2+ -dependent insulin secretion.