NMDA receptors mediate leptin signaling and regulate potassium channel trafficking in pancreatic β-cells

NMDA receptors (NMDARs) are Ca2+-permeant, ligand-gated ion channels activated by the excitatory neurotransmitter glutamate and have well-characterized roles in the nervous system. The expression and function of NMDARs in pancreatic beta-cells, by contrast, are poorly understood. Here, we report a novel function of NMDARs in beta-cells. Using a combination of biochemistry, electrophysiology, and imaging techniques, we now show that NMDARs have a key role in mediating the effect of leptin to modulate beta-cells electrical activity by promoting AMP-activated protein kinase (AMPK)-dependent trafficking of KATP and Kv2.1 channels to the plasma membrane. Blocking NMDAR activity inhibited the ability of leptin to activate AMPK, induce KATP and Kv2.1 channel trafficking, and promote membrane hyperpolarization. Conversely, activation of NMDARs mimicked the effect of leptin, causing Ca2+ influx, AMPK activation, and increased trafficking of KATP and Kv2.1 channels to the plasma membrane, and triggered membrane hyperpolarization. Moreover, leptin potentiated NMDAR currents and triggered NMDAR-dependent Ca2+ influx. Importantly, NMDAR-mediated signaling was observed in rat insulinoma 832/13 cells and in human beta-cells, indicating that this pathway is conserved across species. The ability of NMDARs to regulate potassium channel surface expression and thus, beta-cells excitability provides mechanistic insight into the recently reported insulinotropic effects of NMDAR antagonists and therefore highlights the therapeutic potential of these drugs in managing type 2 diabetes.