Closure by iptakalim, a cardiovascular KATP channel opener, of rat pancreatic β-cell KATP channels and its molecular basis

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概要

• 論文の詳細を見る

• Diabetes mellitus is a group of diseases characterized by high levels of blood glucose resulting from defectsin insulin production, insulin action, or both. Diabetes patients usually have accompanying cardiovascular disorders.Sulfonylureas have been the leading oral antihyperglycemic agents for type 2 diabetes treatment, which currently stillconstitute the most popular anti-diabetic drugs. Nevertheless, concern has arisen over the side eff ects of sulfonylureason the cardiovascular system. Here we report that iptakalim, a novel cardiovascular ATP-sensitive potassium（ KATP）channel opener, closed rat pancreatic β-cell KATP channels and increased insulin release. Using whole-cell patch-clamprecordings, iptakalim depolarized β-cells, induced action potential fi ring and reduced pancreatic KATP channel currents.Using single-channel recordings, iptakalim reduced KATP channel open-probability independently of intracellular ATPconcentrations. We demonstrated that iptakalim elevated intracellular Ca2+ concentrations and increased insulin release asrevealed by fl uorescence imaging（ fura-2） and biochemical measurements, respectively. In addition, iptakalim signifi cantlyinhibited the open-probability of recombinant Kir6.2/SUR1 and Kir6.2FL4A（ a traffi cking mutant of the Kir6.2） channelsexpressed in transfected human embryonic kidney （HEK） 293 cells. Collectively, iptakalim, a cardiovascular KATPchannel opener, closes rat pancreatic β-cell KATP channels, which may result from direct inhibition of the Kir6.2 subunit.Therefore, iptakalim bi-directionally regulates KATP channels in cardiovascular and pancreatic tissues, and this uniquepharmacological property suggests iptakalim could be used as a new therapeutic strategy for the treatment of type 2diabetes with the potential benefi t in alleviating cardiac and/or vascular disorders frequently associated with diabetes.

• 弘前大学の論文

著者

• MISAKI NAOKO

  Department of Health Promotion, Division of Health Sciences, Hirosaki University Graduate School of

• Mao Xia

  Division Of Neurology Barrow Neurological Institute

• Misaki Naoko

  Department Of Health Promotion Division Of Health Sciences Hirosaki University Graduate School Of He

• Misaki Naoko

  Department Of Physiology Hirosaki University Graduate School Of Medicine

• Wu Jie

  Division Of Neurology Barrow Neurological Institute

• Wakui Makoto

  Division of Clinical Research, Hirosaki National Hospital

• Suga Sechiko

  Department of Physilology and Membrane Biology, University of California, Davis, School of Medicine

• Lin Yu-Fung

  Division of Neurology, Barrow Neurological Institute

• Lin Yu-fung

  Division Of Neurology Barrow Neurological Institute

• Wakui Makoto

  Division Of Clinical Research Hirosaki National Hospital

• Suga Sechiko

  Department Of Physilology And Membrane Biology University Of California Davis School Of Medicine

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