Members of the Kv1 and Kv2 voltage-dependent K(+) channel families regulate insulin secretion.
In pancreatic beta-cells, voltage-dependent K(+) (Kv) channels are potential mediators of repolarization, closure of Ca(2+) channels, and limitation of insulin secretion. The specific Kv channels expressed in beta-cells and their contribution to the delayed rectifier current and regulation of insulin secretion in these cells are unclear. High-level protein expression and mRNA transcripts for Kv1.4, 1.6, and 2.1 were detected in rat islets and insulinoma cells. Inhibition of these channels with tetraethylammonium decreased I(DR) by approximately 85% and enhanced glucose-stimulated insulin secretion by 2- to 4-fold. Adenovirus-mediated expression of a C-terminal truncated Kv2.1 subunit, specifically eliminating Kv2 family currents, reduced delayed rectifier currents in these cells by 60-70% and enhanced glucose-stimulated insulin secretion from rat islets by 60%. Expression of a C-terminal truncated Kv1.4 subunit, abolishing Kv1 channel family currents, reduced delayed rectifier currents by approximately 25% and enhanced glucose-stimulated insulin secretion from rat islets by 40%. This study establishes that Kv2 and 1 channel homologs mediate the majority of repolarizing delayed rectifier current in rat beta-cells and that antagonism of Kv2.1 may prove to be a novel glucose-dependent therapeutic treatment for type 2 diabetes.
MacDonald
P E
PE
Department of Medicine, University of Toronto, Toronto Ontario, Canada M5S 1A8.
Ha
X F
XF
Wang
J
J
Smukler
S R
SR
Sun
A M
AM
Gaisano
H Y
HY
Salapatek
A M
AM
Backx
P H
PH
Wheeler
M B
MB
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051668:Delayed Rectifier Potassium Channels; D004553:Electric Conductivity; D017353:Gene Deletion; D015870:Gene Expression; D005822:Genetic Vectors; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051665:Kv1.4 Potassium Channel; D008164:Luminescent Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011994:Recombinant Proteins; D051669:Shab Potassium Channels; D019789:Tetraethylammonium / Q000494:pharmacology; D014162:Transfection
D051668:Delayed Rectifier Potassium Channels; D007328:Insulin; C496979:Kcna4 protein, rat; C496991:Kcnb1 protein, rat; D051665:Kv1.4 Potassium Channel; D008164:Luminescent Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051669:Shab Potassium Channels; D049452:Green Fluorescent Proteins; D019789:Tetraethylammonium; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D005905:Glyburide; D015056:1-Methyl-3-isobutylxanthine