Voltage-gated potassium channel Kv1.3 regulates GLUT4 trafficking to the plasma membrane via a Ca2+-dependent mechanism.
Kv1.3 is a voltage-gated K(+) channel expressed in insulin-sensitive tissues. We previously showed that gene inactivation or pharmacological inhibition of Kv1.3 channel activity increased peripheral insulin sensitivity independently of body weight by augmenting the amount of GLUT4 at the plasma membrane. In the present study, we further examined the effect Kv1.3 on GLUT4 trafficking and tested whether it occurred via an insulin-dependent pathway. We found that Kv1.3 inhibition by margatoxin (MgTX) stimulated glucose uptake in adipose tissue and skeletal muscle and that the effect of MgTX on glucose transport was additive to that of insulin. Furthermore, whereas the increase in uptake was wortmannin insensitive, it was completely inhibited by dantrolene, a blocker of Ca(2+) release from intracellular Ca(2+) stores. In white adipocytes in primary culture, channel inhibition by Psora-4 increased GLUT4 translocation to the plasma membrane. In these cells, GLUT4 protein translocation was unaffected by the addition of wortmannin but was significantly inhibited by dantrolene. Channel inhibition depolarized the membrane voltage and led to sustained, dantrolene-sensitive oscillations in intracellular Ca(2+) concentration. These results indicate that the apparent increase in insulin sensitivity observed in association with inhibition of Kv1.3 channel activity is mediated by an increase in GLUT4 protein at the plasma membrane, which occurs largely through a Ca(2+)-dependent process.
Li
Yanyan
Y
Department of Medicine, Yale University School of Medicine, New Haven, CT 06520-8029, USA.
Wang
Peili
P
Xu
Jianchao
J
Desir
Gary V
GV
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000730:Androstadienes / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism*; D003620:Dantrolene / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009125:Muscle Relaxants, Central / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D041681:NIH 3T3 Cells; D012604:Scorpion Venoms / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D051275:Glucose Transporter Type 4; D007328:Insulin; D051664:Kv1.3 Potassium Channel; D009125:Muscle Relaxants, Central; D012604:Scorpion Venoms; C077910:margatoxin; D003620:Dantrolene; D005947:Glucose; D002118:Calcium; D000077191:Wortmannin