SNAP-25(1-180) enhances insulin secretion by blocking Kv2.1 channels in rat pancreatic islet beta-cells.
Voltage-gated outward K(+) currents from pancreatic islet beta-cells are known to repolarize the action potential during a glucose stimulus, and consequently to modulate Ca(2+) entry and insulin secretion. The voltage gated K(+) (Kv) channel, Kv2.1, which is expressed in rat islet beta-cells, mediates over 60% of the Kv outward K(+) currents. A novel peptidyl inhibitor of Kv2.1/Kv2.2 channels, guangxitoxin (GxTX)-1, has been shown to enhance glucose-stimulated insulin secretion. Here, we show that SNAP-25(1-180) (S180), an N-terminal SNAP-25 domain, but not SNAP-25(1-206) (S206), inhibits Kv current and enhances glucose-dependent insulin secretion from rat pancreatic islet beta-cells, and furthermore, this enhancement was induced by the blockade of the Kv2.1 current. This study indicates that the Kv2.1 channel is a potential target for novel therapeutic agent design for the treatment of type 2 diabetes. This target may possess advantages over currently-used therapies, which modulate insulin secretion in a glucose-independent manner.
Zhuang
Guo-qing
GQ
College of Life Science, Graduate University of the Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, PR China.
Wu
Wei
W
Liu
Fen
F
Ma
Jun-li
JL
Luo
Yan-xia
YX
Xiao
Zhong-xin
ZX
Liu
Yan
Y
Wang
Wei
W
He
Yan
Y
D000818:Animals; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D051669:Shab Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000737:chemistry / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D007328:Insulin; C496991:Kcnb1 protein, rat; D051669:Shab Potassium Channels; D050825:Synaptosomal-Associated Protein 25; D005947:Glucose