Leptin-induced Trafficking of KATP Channels: A Mechanism to Regulate Pancreatic β-cell Excitability and Insulin Secretion

Abstract

The adipocyte hormone leptin was first recognized for its actions in the central nervous system to regulate energy homeostasis but has since been shown to have direct actions on peripheral tissues. In pancreatic β-cells leptin suppresses insulin secretion by increasing K_ATP channel conductance, which causes membrane hyperpolarization and renders β-cells electrically silent. However, the mechanism by which leptin increases K_ATP channel conductance had remained unresolved for many years following the initial observation. Recent studies have revealed that leptin increases surface abundance of K_ATP channels by promoting channel trafficking to the β-cell membrane. Thus, K_ATP channel trafficking regulation has emerged as a mechanism by which leptin increases K_ATP channel conductance to regulate β-cell electrical activity and insulin secretion. This review will discuss the leptin signaling pathway that underlies K_ATP channel trafficking regulation in β-cells.

Keywords: ATP-sensitive potassium (KATP) channel; Insulin secretion; Leptin; β-cell.

Figure 1

Leptin binding to its receptor (OBRb) leads to a calcium influx through calcium-permeant ion channels. The rise in intracellular calcium activates CaMKKβ which then phosphorylates and activates AMPK. Downstream of AMPK actin remodeling is triggered through PTEN inhibition and activation of PKA. Depolymerization of the cortical actin cytoskeleton allows vesicles containing K_ATP channels to traffic to the membrane. The increased abundance of K_ATP channels reduces β-cell excitability thereby suppressing insulin secretion. Abbreviations: Extracellular (Ext.), Intracellular (Int.), N-methyl-d-Aspartate Receptor (NMDAR), Calcium (Ca²⁺), Janus Kinase (JAK), Ca²⁺/calmodulin kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), Leptin receptor (OBRb), phosphoinositide 3-kinase (PI3K), phosphatidylinositol (4,5)-bisphosphate (PIP2), phosphatidylinositol (3,4,5)-trisphosphate (PIP3), phosphatase and tensin homolog (PTEN), Glycogen synthase kinase 3 β (GSK3β), cAMP-dependent protein kinase A (PKA), Transient receptor potential channel 4 (TRPC4), Potassium (K⁺).