Cdk5-dependent regulation of glucose-stimulated insulin secretion

Fan Yan Wei, Kazuaki Nagashima, Toshio Ohshima, Yasunori Saheki, Yun Fei Lu, Masayuki Matsushita, Yuichiro Yamada, Katsuhiko Mikoshiba, Yutaka Seino, Hideki Matsui, Kazuhito Tomizawa

Research output: Contribution to journalArticle

131 Citations (Scopus)

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 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 α(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.

Original languageEnglish
Pages (from-to)1104-1108
Number of pages5
JournalNature Medicine
Volume11
Issue number10
DOIs
Publication statusPublished - 2005 Oct
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase 5
Insulin
Glucose
Insulin-Secreting Cells
Electric potential
Adenosine Triphosphate
SNARE Proteins
Phosphorylation
Drug and Narcotic Control
Medical problems
Islets of Langerhans
Hypoglycemia
Knockout Mice
Hyperglycemia
Diabetes Mellitus
Phosphotransferases
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Wei, F. Y., Nagashima, K., Ohshima, T., Saheki, Y., Lu, Y. F., Matsushita, M., ... Tomizawa, K. (2005). Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nature Medicine, 11(10), 1104-1108. https://doi.org/10.1038/nm1299

Cdk5-dependent regulation of glucose-stimulated insulin secretion. / Wei, Fan Yan; Nagashima, Kazuaki; Ohshima, Toshio; Saheki, Yasunori; Lu, Yun Fei; Matsushita, Masayuki; Yamada, Yuichiro; Mikoshiba, Katsuhiko; Seino, Yutaka; Matsui, Hideki; Tomizawa, Kazuhito.

In: Nature Medicine, Vol. 11, No. 10, 10.2005, p. 1104-1108.

Research output: Contribution to journalArticle

Wei, FY, Nagashima, K, Ohshima, T, Saheki, Y, Lu, YF, Matsushita, M, Yamada, Y, Mikoshiba, K, Seino, Y, Matsui, H & Tomizawa, K 2005, 'Cdk5-dependent regulation of glucose-stimulated insulin secretion' Nature Medicine, vol. 11, no. 10, pp. 1104-1108. https://doi.org/10.1038/nm1299
Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M et al. Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nature Medicine. 2005 Oct;11(10):1104-1108. https://doi.org/10.1038/nm1299
Wei, Fan Yan ; Nagashima, Kazuaki ; Ohshima, Toshio ; Saheki, Yasunori ; Lu, Yun Fei ; Matsushita, Masayuki ; Yamada, Yuichiro ; Mikoshiba, Katsuhiko ; Seino, Yutaka ; Matsui, Hideki ; Tomizawa, Kazuhito. / Cdk5-dependent regulation of glucose-stimulated insulin secretion. In: Nature Medicine. 2005 ; Vol. 11, No. 10. pp. 1104-1108.
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