AKAP79/150 coordinates leptin-induced PKA activation to regulate KATPchannel trafficking in pancreatic β-cells

Abstract

AbstractThe adipocyte hormone leptin regulates glucose homeostasis both centrally and peripherally. A key peripheral target is the pancreatic β-cell, which secretes insulin upon glucose stimulation. Leptin suppresses glucose-stimulated insulin secretion by promoting trafficking of KATPchannels to the β-cell surface, which increases K+conductance and causes β-cell hyperpolarization. Here we investigate the signaling mechanism underlying leptin-induced KATPchannel translocation with a focus on protein kinase A (PKA). Using FRET-based PKA activity reporters, we show that leptin increases PKA activity at the cell membrane via a signaling pathway involving NMDA receptors, CaMKKβ and AMPK. Genetic knockdown and rescue experiments reveal that leptin activation of PKA requires tethering of PKA to the membrane-targeted PKA-anchoring protein AKAP79/150. Interestingly, disrupting protein phosphatase 2B (PP2B) anchoring to AKAP79/150, known to elevate basal PKA signaling, increases surface KATPchannels. Our findings uncover a novel role of AKAP79/150 in coordinating leptin and PKA signaling to regulate β-cell function.