The β-cell GHSR and downstream cAMP/TRPM2 signaling account for insulinostatic and glycemic effects of ghrelin.
The β-cell GHSR and downstream cAMP/TRPM2 signaling account for insulinostatic and glycemic effects of ghrelin.
复制标题
DOI：
10.1038/srep14041
复制
发表时间：
2015-09-15
影响因子：
4.6
通讯作者：
Yada T
中科院分区：
文献类型：
--
作者：
Kurashina T;Dezaki K;Yoshida M;Sukma Rita R;Ito K;Taguchi M;Miura R;Tominaga M;Ishibashi S;Kakei M;Yada T
胃激素ghrelin调节胰岛素分泌，以及生长激素释放，进食行为和肥胖。Ghrelin通过与生长激素促分泌素受体（GHSR）结合Gq/11蛋白信号传导发挥其生物学作用。相比之下，生长素释放肽通过Gi蛋白介导的信号传导作用于胰岛β细胞。这些观察结果提出了一个问题，即ghrelin对胰岛β细胞的作用是否涉及非典型GHSR和/或不同的信号转导。此外，β-细胞GHSR在生长素释放肽的全身血糖效应中的作用仍有待确定。为了解决这些问题，本研究采用了全球GHSR缺失小鼠和在β细胞中选择性重新表达GHSR的小鼠。我们在此报告，ghrelin通过与普通GHSR的直接相互作用减弱葡萄糖诱导的胰岛素释放，所述普通GHSR独特地偶联至β细胞中的新型cAMP/TRPM 2信号传导，并且这种具有独特的胰岛素抑制信号传导的β细胞GHSR在很大程度上解释了ghrelin对循环葡萄糖和胰岛素水平的全身效应。新型β细胞特异性GHSR-cAMP/TRPM 2信号传导为2型糖尿病的治疗提供了潜在的治疗靶点。
Gastric hormone ghrelin regulates insulin secretion, as well as growth hormone release, feeding behavior and adiposity. Ghrelin is known to exert its biological actions by interacting with the growth hormone secretagogue-receptor (GHSR) coupled to Gq/11-protein signaling. By contrast, ghrelin acts on pancreatic islet β-cells via Gi-protein-mediated signaling. These observations raise a question whether the ghrelin action on islet β-cells involves atypical GHSR and/or distinct signal transduction. Furthermore, the role of the β-cell GHSR in the systemic glycemic effect of ghrelin still remains to be defined. To address these issues, the present study employed the global GHSR-null mice and those re-expressing GHSR selectively in β-cells. We here report that ghrelin attenuates glucose-induced insulin release via direct interaction with ordinary GHSR that is uniquely coupled to novel cAMP/TRPM2 signaling in β-cells, and that this β-cell GHSR with unique insulinostatic signaling largely accounts for the systemic effects of ghrelin on circulating glucose and insulin levels. The novel β-cell specific GHSR-cAMP/TRPM2 signaling provides a potential therapeutic target for the treatment of type 2 diabetes.