Nature Medicine 11, 1104 - 1108 (2005)
Published online: 11 September 2005; | doi:10.1038/nm1299
Cdk5-dependent regulation of glucose-stimulated insulin secretionFan-Yan Wei1, Kazuaki Nagashima2, Toshio Ohshima3, Yasunori Saheki1, Yun-Fei Lu4, Masayuki Matsushita1, Yuichiro Yamada2, Katsuhiko Mikoshiba3, Yutaka Seino2, Hideki Matsui1, 4
& Kazuhito Tomizawa11
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan. 2
Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. 3
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Saitama 351-0198, Japan. 4
Protein Therapy, Preventure Program, Office of Technology Transfer, Japan Science and Technology Corporation, Okayama 700-8558, Japan.
Correspondence should be addressed to Kazuhito Tomizawa tomikt@md.okayama-u.ac.jp Tight glycemic control in individuals with diabetes mellitus is essential to prevent or delay its complications1. 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  1C 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.
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