title: Concerted Trafficking Regulation of Kv2.1 and KATP Channels by Leptin in Pancreatic β-Cells.
abstract: In pancreatic β-cells, voltage-gated potassium 2.1 (Kv2.1) channels are the dominant delayed rectifier potassium channels responsible for action potential repolarization. Here, we report that leptin, a hormone secreted by adipocytes known to inhibit insulin secretion, causes a transient increase in surface expression of Kv2.1 channels in rodent and human β-cells. The effect of leptin on Kv2.1 surface expression is mediated by the AMP-activated protein kinase (AMPK). Activation of AMPK mimics whereas inhibition of AMPK occludes the effect of leptin. Inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase β, a known upstream kinase of AMPK, also blocks the effect of leptin. In addition, the cAMP-dependent protein kinase (PKA) is involved in Kv2.1 channel trafficking regulation. Inhibition of PKA prevents leptin or AMPK activators from increasing Kv2.1 channel density, whereas stimulation of PKA is sufficient to promote Kv2.1 channel surface expression. The increased Kv2.1 surface expression by leptin is dependent on actin depolymerization, and pharmacologically induced actin depolymerization is sufficient to enhance Kv2.1 surface expression. The signaling and cellular mechanisms underlying Kv2.1 channel trafficking regulation by leptin mirror those reported recently for ATP-sensitive potassium (KATP) channels, which are critical for coupling glucose stimulation with membrane depolarization. We show that the leptin-induced increase in surface KATP channels results in more hyperpolarized membrane potentials than control cells at stimulating glucose concentrations, and the increase in Kv2.1 channels leads to a more rapid repolarization of membrane potential in cells firing action potentials. This study supports a model in which leptin exerts concerted trafficking regulation of KATP and Kv2.1 channels to coordinately inhibit insulin secretion.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 and shyngs@ohsu.edu.
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Shyng
authors.affiliation: the Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan pcchen@mail.ncku.edu.tw.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chen
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects*; D051669:Shab Potassium Channels / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; D015221:Potassium Channels; D051669:Shab Potassium Channels; C117780:mitochondrial K(ATP) channel; D012964:Sodium; D017868:Cyclic AMP-Dependent Protein Kinases; D000263:Adenylate Kinase; D002118:Calcium
keywords: AMP-activated kinase (AMPK); F-actin; cytoskeleton; potassium channel; protein kinase A (PKA); trafficking