Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis.
Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis.
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DOI：
10.1371/journal.pone.0015553
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发表时间：
2010-12-09
期刊：
影响因子：
3.7
通讯作者：
Nagamatsu S
中科院分区：
文献类型：
--
作者：
Ohara-Imaizumi M;Yoshida M;Aoyagi K;Saito T;Okamura T;Takenaka H;Akimoto Y;Nakamichi Y;Takanashi-Yanobu R;Nishiwaki C;Kawakami H;Kato N;Hisanaga S;Kakei M;Nagamatsu S
据报道，CDKAL1基因的变异与2型糖尿病相关，而胰岛素在人类中的释放降低。我们研究了CDKAL1基因基因敲除（CDKAL1 KO）小鼠中的胰岛素释放谱。
CDKAL1 KOβ细胞的总反射荧光成像显示，在第一阶段胰岛素释放期间的融合事件数量减少了，但是，第二阶段释放期间融合事件的数量没有显着差异。在高葡萄糖刺激期间，WT和KO细胞之间的cdkal1缺失导致延迟且胞质的ca2+浓度缓慢揭示了ATP敏感的K+（KATP）通道对葡萄糖的反应性在KO细胞中被钝化，尽管CDKAL1与细胞周期蛋白依赖性激酶5（CDK5）相同。 1，WT和CDKAL1 KO ISLET之间CDK5的激酶活性没有差异。
我们提供了描述CDKAL1在β细胞中的功能的第一份报告。规定。
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. 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 Ca2+ concentration during high glucose stimulation. Patch-clamp experiments revealed that the responsiveness of ATP-sensitive K+ (KATP) 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. 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, KATP channel responsiveness and the subsequent activity of Ca2+ channels through pathways other than CDK5-mediated regulation.
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影响因子：
7.7
作者：
Chen, LY;Koh, DS;Hille, B
通讯作者：
Hille, B
影响因子：
7.7
作者：
Takeuchi F;Serizawa M;Yamamoto K;Fujisawa T;Nakashima E;Ohnaka K;Ikegami H;Sugiyama T;Katsuya T;Miyagishi M;Nakashima N;Nawata H;Nakamura J;Kono S;Takayanagi R;Kato N
通讯作者：
Kato N
影响因子：
4.8
作者：
Ohara-Imaizumi, M;Nakamichi, Y;Nagamatsu, S
通讯作者：
Nagamatsu, S
影响因子：
4.8
作者：
Hughes, E;Lee, AK;Tse, A
通讯作者：
Tse, A
影响因子：
4.8
作者：
Dukes, ID;Sreenan, S;Polonsky, KS
通讯作者：
Polonsky, KS