Insulin suppresses IKs (KCNQ1/KCNE1) currents, which require β-subunit KCNE1.
Abnormal QT prolongation in diabetic patients has become a clinical problem because it increases the risk of lethal ventricular arrhythmia. In an animal model of type 1 diabetes mellitus, several ion currents, including the slowly activating delayed rectifier potassium current (IKs), are altered. The IKs channel is composed of KCNQ1 and KCNE1 subunits, whose genetic mutations are well known to cause long QT syndrome. Although insulin is known to affect many physiological and pathophysiological events in the heart, acute effects of insulin on cardiac ion channels are poorly understood at present. This study was designed to investigate direct electrophysiological effects of insulin on IKs (KCNQ1/KCNE1) currents. KCNQ1 and KCNE1 were co-expressed in Xenopus oocytes, and whole cell currents were measured by a two-microelectrode voltage-clamp method. Acute application of insulin suppressed the KCNQ1/KCNE1 currents and phosphorylated Akt and extracellular signal-regulated kinase (ERK), the two major downstream effectors, in a concentration-dependent manner. Wortmannin (10(-6) M), a phosphoinositide 3-kinase (PI3K) inhibitor, attenuated the suppression of the currents and phosphorylation of Akt by insulin, whereas U0126 (10(-5) M), a mitogen-activated protein kinase kinase (MEK) inhibitor, had no effect on insulin-induced suppression of the currents. In addition, insulin had little effect on KCNQ1 currents without KCNE1, which indicated an essential role of KCNE1 in the acute suppressive effects of insulin. Mutagenesis studies revealed amino acid residues 111-118 within the distal third C-terminus of KCNE1 as an important region. Insulin has direct electrophysiological effects on IKs currents, which may affect cardiac excitability.
Department of Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
Minghua
M
Wu
Yutaro
Y
Obara
Ikuo
I
Norota
Yoshinobu
Y
Nagasawa
Kuniaki
K
Ishii
D000200:Action Potentials / Q000187:drug effects*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002070:Butadienes / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051657:KCNQ1 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000077191:Wortmannin; D014981:Xenopus
D000730:Androstadienes; D002070:Butadienes; D007328:Insulin; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009570:Nitriles; D024642:Potassium Channels, Voltage-Gated; D047428:Protein Kinase Inhibitors; C113580:U 0126; D000077191:Wortmannin