Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis.
<h4>Background</h4>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 β cells is largely unknown. Therefore, to determine the role of CDKAL1 in insulin release from β cells, we studied insu...
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2010
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oai:doaj.org-article:26645a16c5be489a9a8fe1a5189a385b2021-11-18T07:01:53ZDeletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis.1932-620310.1371/journal.pone.0015553https://doaj.org/article/26645a16c5be489a9a8fe1a5189a385b2010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21151568/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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 β cells is largely unknown. Therefore, to determine the role of CDKAL1 in insulin release from β cells, we studied insulin release profiles in CDKAL1 gene knockout (CDKAL1 KO) mice.<h4>Principal findings</h4>Total internal reflection fluorescence imaging of CDKAL1 KO β 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.<h4>Conclusions/significance</h4>We provide the first report describing the function of CDKAL1 in β cells. Our results indicate that CDKAL1 controls first-phase insulin exocytosis in β cells by facilitating ATP generation, K(ATP) channel responsiveness and the subsequent activity of Ca(2+) channels through pathways other than CDK5-mediated regulation.Mica Ohara-ImaizumiMasashi YoshidaKyota AoyagiTaro SaitoTadashi OkamuraHitoshi TakenakaYoshihiro AkimotoYoko NakamichiRieko Takanashi-YanobuChiyono NishiwakiHayato KawakamiNorihiro KatoShin-ichi HisanagaMasafumi KakeiShinya NagamatsuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 12, p e15553 (2010) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Mica Ohara-Imaizumi Masashi Yoshida Kyota Aoyagi Taro Saito Tadashi Okamura Hitoshi Takenaka Yoshihiro Akimoto Yoko Nakamichi Rieko Takanashi-Yanobu Chiyono Nishiwaki Hayato Kawakami Norihiro Kato Shin-ichi Hisanaga Masafumi Kakei Shinya Nagamatsu Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. |
| description |
<h4>Background</h4>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 β cells is largely unknown. Therefore, to determine the role of CDKAL1 in insulin release from β cells, we studied insulin release profiles in CDKAL1 gene knockout (CDKAL1 KO) mice.<h4>Principal findings</h4>Total internal reflection fluorescence imaging of CDKAL1 KO β 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.<h4>Conclusions/significance</h4>We provide the first report describing the function of CDKAL1 in β cells. Our results indicate that CDKAL1 controls first-phase insulin exocytosis in β cells by facilitating ATP generation, K(ATP) channel responsiveness and the subsequent activity of Ca(2+) channels through pathways other than CDK5-mediated regulation. |
| format |
article |
| author |
Mica Ohara-Imaizumi Masashi Yoshida Kyota Aoyagi Taro Saito Tadashi Okamura Hitoshi Takenaka Yoshihiro Akimoto Yoko Nakamichi Rieko Takanashi-Yanobu Chiyono Nishiwaki Hayato Kawakami Norihiro Kato Shin-ichi Hisanaga Masafumi Kakei Shinya Nagamatsu |
| author_facet |
Mica Ohara-Imaizumi Masashi Yoshida Kyota Aoyagi Taro Saito Tadashi Okamura Hitoshi Takenaka Yoshihiro Akimoto Yoko Nakamichi Rieko Takanashi-Yanobu Chiyono Nishiwaki Hayato Kawakami Norihiro Kato Shin-ichi Hisanaga Masafumi Kakei Shinya Nagamatsu |
| author_sort |
Mica Ohara-Imaizumi |
| title |
Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. |
| title_short |
Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. |
| title_full |
Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. |
| title_fullStr |
Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. |
| title_full_unstemmed |
Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. |
| title_sort |
deletion of cdkal1 affects mitochondrial atp generation and first-phase insulin exocytosis. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2010 |
| url |
https://doaj.org/article/26645a16c5be489a9a8fe1a5189a385b |
| work_keys_str_mv |
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| _version_ |
1718424029624270848 |