| First Author | Ohara-Imaizumi M | Year | 2010 |
| Journal | PLoS One | Volume | 5 |
| Issue | 12 | Pages | e15553 |
| PubMed ID | 21151568 | Mgi Jnum | J:167737 |
| Mgi Id | MGI:4879060 | Doi | 10.1371/journal.pone.0015553 |
| Citation | Ohara-Imaizumi M, et al. (2010) Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. PLoS One 5(12):e15553 |
| abstractText | BACKGROUND: A variant of the CDKAL1 gene was reported to be associated with type 2 diabetes and reduced insulin release in humans; however, the role of CDKAL1 in beta cells is largely unknown. Therefore, to determine the role of CDKAL1 in insulin release from beta cells, we studied insulin release profiles in CDKAL1 gene knockout (CDKAL1 KO) mice. PRINCIPAL FINDINGS: Total internal reflection fluorescence imaging of CDKAL1 KO beta cells showed that the number of fusion events during first-phase insulin release was reduced. However, there was no significant difference in the number of fusion events during second-phase release or high K(+)-induced release between WT and KO cells. CDKAL1 deletion resulted in a delayed and slow increase in cytosolic free Ca(2+) concentration during high glucose stimulation. Patch-clamp experiments revealed that the responsiveness of ATP-sensitive K(+) (K(ATP)) channels to glucose was blunted in KO cells. In addition, glucose-induced ATP generation was impaired. Although CDKAL1 is homologous to cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1, there was no difference in the kinase activity of CDK5 between WT and CDKAL1 KO islets. CONCLUSIONS/SIGNIFICANCE: We provide the first report describing the function of CDKAL1 in beta cells. Our results indicate that CDKAL1 controls first-phase insulin exocytosis in beta cells by facilitating ATP generation, K(ATP) channel responsiveness and the subsequent activity of Ca(2+) channels through pathways other than CDK5-mediated regulation. |
