SSTR 2 is the functionally dominant somatostatin receptor in human 2 pancreatic β - and α - cells 3 4

20 Somatostatin-14 (SST) inhibits insulin and glucagon secretion by activating G-protein coupled 21 somatostatin receptors (SSTRs), of which 5 isoforms exist (SSTR1-5). In mice, the effects on 22 pancreatic β-cells are mediated by SSTR5, whereas α-cells express SSTR2. In both cell types, 23 SSTR activation results in membrane hyperpolarisation and suppression of exocytosis. Here we 24 examined the mechanisms by which SST inhibits secretion from human βand α-cells, and the 25 SSTR isoforms mediating these effects. Quantitative PCR revealed high expression of SSTR2, 26 with lower levels of SSTR1, SSTR3 and SSTR5, in human islets. Immunohistochemistry showed 27 expression of SSTR2 in both βand α-cells. SST application hyperpolarized human β-cells and 28 inhibited action potential firing. The membrane hyperpolarization was unaffected by tolbutamide 29 but antagonized by tertiapin-Q, a blocker of G-protein gated inwardly-rectifying K-channels 30 (GIRK). The effect of SST was mimicked by an SSTR2-selective agonist while a SSTR5 agonist 31 was marginally effective. SST strongly (>70%) reduced depolarization-evoked exocytosis in 32 both βand α-cells. A slightly weaker inhibition was observed in both cell types after SSTR2 33 activation. SSTR3and SSTR1-selective agonists moderately reduced the exocytotic responses 34 in βand α-cells, respectively, whereas SSTR4and SSTR5-specific agonists were ineffective. 35 SST also reduced voltage-gated P/Q-type Ca-currents in β-cells, but normalization of Ca 36 influx to control levels by prolonged depolarizations only partially restored exocytosis. We 37 conclude that SST inhibits secretion from both human βand α-cells by activating GIRK and 38 suppressing electrical activity, reducing P/Q-type Ca-currents and directly inhibiting 39 exocytosis. These effects are predominantly mediated by SSTR2 in both cell types. 40 41