SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells
SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells
复制标题
DOI：
10.1152/ajpendo.00207.2012
复制
发表时间：
2012-11-01
影响因子：
5.1
通讯作者：
Braun, Matthias
中科院分区：
文献类型：
--
作者：
Kailey, Balrik;van de Bunt, Martijn;Braun, Matthias
Kailey B, van de Bunt M, Cheley S, Johnson PR, MacDonald PE, Gloyn AL, Rorsman P, Braun M. SSTR2是人胰腺β和α细胞中功能优势的生长抑素受体。[J] .中国生物医学工程学报，2016,31(2):387 - 398。首次发表于2012年8月28日；doi: 10.1152 / ajpendo.00207.2012。-生长抑素-14 （SST）通过激活G蛋白偶联的生长抑素受体（SSTRs）抑制胰岛素和胰高血糖素的分泌，其中存在5种亚型（SSTR1-5）。在小鼠中，对胰腺β细胞的影响是由SSTR5介导的，而α细胞表达SSTR2。在这两种细胞类型中，SSTR激活导致膜超极化和胞吐抑制。在这里，我们研究了SST抑制人类β细胞和α细胞分泌的机制，以及介导这些作用的SSTR亚型。定量PCR结果显示，SSTR2在人胰岛中高表达，而SSTR1、SSTR3和SSTR5的表达水平较低。免疫组织化学显示SSTR2在β细胞和α细胞中均有表达。SST应用超极化人β细胞并抑制动作电位放电。膜超极化不受甲磺丁胺的影响，但可被G蛋白门控内向纠偏K+通道（GIRK）阻滞剂terapin - q拮抗。SST的作用被一种sstr2选择性激动剂所模拟，而SSTR5激动剂的作用则微乎其微。在β和α细胞中，SST强烈（bb0 70%）减少了去极化诱发的胞吐。SSTR2激活后，两种细胞类型的抑制作用稍弱。SSTR3-和sstr1选择性激动剂分别适度降低β细胞和α细胞的胞吐反应，而SSTR4-和sstr5特异性激动剂无效。SST还降低了β细胞中的电压门控P/ q型Ca2+电流，但通过延长去极化使Ca2+内流正常化以控制水平仅部分恢复胞外分泌。我们得出结论，SST通过激活GIRK和抑制电活动、减少P/ q型Ca2+电流和直接抑制胞外分泌来抑制人类β细胞和α细胞的分泌。在两种细胞类型中，这些作用主要由SSTR2介导。
Kailey B, van de Bunt M, Cheley S, Johnson PR, MacDonald PE, Gloyn AL, Rorsman P, Braun M. SSTR2 is the functionally dominant somatostatin receptor in human pancreatic beta- and alpha-cells. Am J Physiol Endocrinol Metab 303: E1107-E1116, 2012. First published August 28, 2012; doi:10.1152/ajpendo.00207.2012.-Somatostatin-14 (SST) inhibits insulin and glucagon secretion by activating G protein-coupled somatostatin receptors (SSTRs), of which five isoforms exist (SSTR1-5). In mice, the effects on pancreatic beta-cells are mediated by SSTR5, whereas alpha-cells express SSTR2. In both cell types, SSTR activation results in membrane hyperpolarization and suppression of exocytosis. Here, we examined the mechanisms by which SST inhibits secretion from human beta- and alpha-cells and the SSTR isoforms mediating these effects. Quantitative PCR revealed high expression of SSTR2, with lower levels of SSTR1, SSTR3, and SSTR5, in human islets. Immunohistochemistry showed expression of SSTR2 in both beta- and alpha-cells. SST application hyperpolarized human beta-cells and inhibited action potential firing. The membrane hyperpolarization was unaffected by tolbutamide but antagonized by tertiapin-Q, a blocker of G protein-gated inwardly rectifying K+ channels (GIRK). The effect of SST was mimicked by an SSTR2-selective agonist, whereas a SSTR5 agonist was marginally effective. SST strongly (>70%) reduced depolarization-evoked exocytosis in both beta- and alpha-cells. A slightly weaker inhibition was observed in both cell types after SSTR2 activation. SSTR3- and SSTR1-selective agonists moderately reduced the exocytotic responses in beta- and alpha-cells, respectively, whereas SSTR4- and SSTR5-specific agonists were ineffective. SST also reduced voltage-gated P/Q-type Ca2+ currents in beta-cells, but normalization of Ca2+ influx to control levels by prolonged depolarizations only partially restored exocytosis. We conclude that SST inhibits secretion from both human beta- and alpha-cells by activating GIRK and suppressing electrical activity, reducing P/Q-type Ca2+ currents, and directly inhibiting exocytosis. These effects are mediated predominantly by SSTR2 in both cell types.