title: Cdk5-dependent regulation of glucose-stimulated insulin secretion.
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(+) (K(ATP)) 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 Ca(2+) channel current and increased Ca(2+) influx across the L-type voltage-dependent Ca(2+) channel (L-VDCC) upon stimulation with high glucose in beta cells, but had no effect on Ca(2+) influx without glucose stimulation. The inhibitory regulation by Cdk5 on the L-VDCC was attributed to the phosphorylation of loop II-III of the alpha(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.
authors.affiliation: Department of Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Fan-Yan
authors.initials: FY
authors.lastname: Wei
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nagashima
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Saheki
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Lu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsui
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tomizawa
mesh_terms: D000818:Animals; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007701:Kinetin; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); C090046:olomoucine; D051360:Cyclin-Dependent Kinase 5; D005947:Glucose; D007701:Kinetin