TITLE

Cdk5-dependent regulation of glucose-stimulated insulin secretion

AUTHOR(S)
Fan-Yan Wei; Nagashima, Kazuaki; Ohshima, Toshio; Saheki, Yasunori; Yun-Fei Lu; Matsushita, Masayuki; Yamada, Yuichiro; Mikoshiba, Katsuhiko; Seino, Yutaka; Matsui, Hideki; Tomizawa, Kazuhito
PUB. DATE
October 2005
SOURCE
Nature Medicine;Oct2005, Vol. 11 Issue 10, p1104
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Tight glycemic control in individuals with diabetes mellitus is essential to prevent or delay its complications. Present treatments to reduce hyperglycemia mainly target the ATP-sensitive K+ (KATP) channel of pancreatic beta cells to increase insulin secretion. These current approaches are often associated with the side effect of hypoglycemia. Here we show that inhibition of the activity of cyclin-dependent kinase 5 (Cdk5) enhanced insulin secretion under conditions of stimulation by high glucose but not low glucose in MIN6 cells and pancreatic islets. The role of Cdk5 in regulation of insulin secretion was confirmed in pancreatic beta cells deficient in p35, an activator of Cdk5. p35-knockout mice also showed enhanced insulin secretion in response to a glucose challenge. Cdk5 kinase inhibition enhanced the inward whole-cell Ca2+ channel current and increased Ca2+ influx across the L-type voltage-dependent Ca2+ channel (L-VDCC) upon stimulation with high glucose in beta cells, but had no effect on Ca2+ influx without glucose stimulation. The inhibitory regulation by Cdk5 on the L-VDCC was attributed to the phosphorylation of loop II-III of the α1C subunit of L-VDCC at Ser783, which prevented the binding to SNARE proteins and subsequently resulted in a decrease of the activity of L-VDCC. These results suggest that Cdk5/p35 may be a drug target for the regulation of glucose-stimulated insulin secretion.
ACCESSION #
18506836

 

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