RT Journal Article
SR Electronic
T1 The Role of Voltage-Gated Potassium Channels Kv2.1 and Kv2.2 in the Regulation of Insulin and Somatostatin Release from Pancreatic Islets
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 407
OP 416
DO 10.1124/jpet.112.199083
VO 344
IS 2
A1 Xiaoyan (Nina) Li
A1 James Herrington
A1 Aleksandr Petrov
A1 Lan Ge
A1 George Eiermann
A1 Yusheng Xiong
A1 Mette V. Jensen
A1 Hans E. Hohmeier
A1 Christopher B. Newgard
A1 Maria L. Garcia
A1 Michael Wagner
A1 Bei B. Zhang
A1 Nancy A. Thornberry
A1 Andrew D. Howard
A1 Gregory J. Kaczorowski
A1 Yun-Ping Zhou
YR 2013
UL http://jpet.aspetjournals.org/content/344/2/407.abstract
AB The voltage-gated potassium channels Kv2.1 and Kv2.2 are highly expressed in pancreatic islets, yet their contribution to islet hormone secretion is not fully understood. Here we investigate the role of Kv2 channels in pancreatic islets using a combination of genetic and pharmacologic approaches. Pancreatic β-cells from Kv2.1−/− mice possess reduced Kv current and display greater glucose-stimulated insulin secretion (GSIS) relative to WT β-cells. Inhibition of Kv2.x channels with selective peptidyl [guangxitoxin-1E (GxTX-1E)] or small molecule (RY796) inhibitors enhances GSIS in isolated wild-type (WT) mouse and human islets, but not in islets from Kv2.1−/− mice. However, in WT mice neither inhibitor improved glucose tolerance in vivo. GxTX-1E and RY796 enhanced somatostatin release in isolated human and mouse islets and in situ perfused pancreata from WT and Kv2.1−/− mice. Kv2.2 silencing in mouse islets by adenovirus-small hairpin RNA (shRNA) specifically enhanced islet somatostatin, but not insulin, secretion. In mice lacking somatostatin receptor 5, GxTX-1E stimulated insulin secretion and improved glucose tolerance. Collectively, these data show that Kv2.1 regulates insulin secretion in β-cells and Kv2.2 modulates somatostatin release in δ-cells. Development of selective Kv2.1 inhibitors without cross inhibition of Kv2.2 may provide new avenues to promote GSIS for the treatment of type 2 diabetes.