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J. Biol. Chem., Vol. 281, Issue 19, 13015-13020, May 12, 2006

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Essential Role of Ubiquitin-Proteasome System in Normal Regulation of Insulin Secretion^*

Miho Kawaguchi¹, Kohtaro Minami^¶1, Kazuaki Nagashima^||, and Susumu Seino^¶2

From the Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, the ^¶Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto 606-8507, Japan, Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, and the ^||Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan

Insulin secretion from pancreatic -cells occurs by sequential cellular processes, including glucose metabolism, electrical activity, Ca²⁺ entry, and regulated exocytosis. Abnormalities in any of these functions can impair insulin secretion. In the present study, we demonstrate that inhibition of proteasome activity severely reduces insulin secretion in the mouse pancreatic -cell line MIN6-m9. Although no significant effects on glucose metabolism including ATP production were found in the presence of proteasome inhibitors, both glucose- and KCl-induced Ca²⁺ entry were drastically reduced. As Ca²⁺-ionophore-induced insulin secretion was unaffected by proteasome inhibition, a defect in Ca²⁺ entry through voltage-dependent calcium channels (VDCCs) is the likely cause of the impaired insulin secretion. We found that the pore-forming -subunit of VDCCs undergoes ubiquitination, which does not decrease but slightly increases expression of the -subunit protein at the plasma membrane. However, electrophysiological analysis revealed that treatment with proteasome inhibitors results in a severe reduction in VDCC activity in MIN6-m9 cells, indicating that VDCC function is suppressed by proteasome inhibition. Furthermore, insulin secretion in isolated mouse pancreatic islets was also decreased by proteasome inhibition. These results demonstrate that the ubiquitin-proteasome system plays a critical role in insulin secretion by maintaining normal function of VDCCs.

Received for publication, February 8, 2006 , and in revised form, March 13, 2006.

^* This work was supported by grant-in-aid for Specially Promoted Research and a grant for 21st Century Center of Excellence program from the Ministry of Education, Culture, Sports, Science and Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. Tel.: 81-78-382-5360; Fax: 81-78-382-5370; E-mail: seino{at}med.kobe-u.ac.jp.

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