AMPK regulates K(ATP) channel trafficking via PTEN inhibition in leptin-treated pancreatic β-cells

Abstract

Leptin regulates pancreatic β-cell excitability through AMP-activated protein kinase (AMPK)-mediated ATP-sensitive potassium (KATP) channel trafficking. However, the signaling components connecting AMPK to KATP channel trafficking are not identified. In this study, we discovered that AMPK inhibits phosphatase and tensin homologue (PTEN) via glycogen synthase kinase 3β (GSK3β) and this signaling pathway is crucial for KATP channel trafficking in leptin-treated pancreatic β-cells. Pharmacologic or genetic inhibition of AMPK or GSK3β, but not casein kinase 2 (CK2), impaired leptin-induced PTEN inactivation and thereby KATP channel trafficking. The PTEN mutant lacking both protein and lipid phosphatase activity is sufficient to induce KATP channel trafficking without leptin. These results present a novel signaling mechanism that underlies leptin regulation of KATP channel trafficking in pancreatic β-cells. Our findings assist in gaining a broader perspective on the peripheral action of leptin on pancreatic β-cell physiology and glucose homeostasis.

Keywords: AMP-activated protein kinase; AMPK; ATP-sensitive potassium channel; CK2; GSK3β; K(ATP) channel; Leptin; PTEN; Pancreatic β-cell; TSC2; casein kinase 2; glycogen synthase kinase 3β; mTORC1; mammalian target of rapamycin complex 1; phosphatase and tensin homologue; tuberous sclerosis 2.