TY - JOUR T1 - Somatostatin Increases Phospholipase D Activity and Phosphatidylinositol 4,5-bisphosphate Synthesis in Clonal β Cells HIT-T15 JF - Molecular Pharmacology JO - Mol Pharmacol SP - 2162 LP - 2172 DO - 10.1124/mol.104.010470 VL - 67 IS - 6 AU - Henrique Cheng AU - Justin A. Grodnitzky AU - Sirintorn Yibchok-anun AU - Jing Ding AU - Walter H. Hsu Y1 - 2005/06/01 UR - http://molpharm.aspetjournals.org/content/67/6/2162.abstract N2 - In the presence of arginine vasopressin (AVP), somatostatin increases [Ca2+]i, leading to a transient increase in insulin release from clonal β cells HIT-T15 via Gi/o and phospholipase C (PLC) pathway (Cheng et al., 2002a). The present study was to elucidate the mechanisms underlying somatostatin-induced [Ca2+]i increase in the presence of AVP. We found that the effect of somatostatin was mediated by βγ subunits but not by the α subunit of Gi/o. Because somatostatin alone failed to increase [Ca2+]i, we hypothesized that somatostatin increases phosphatidylinositol 4,5-bisphosphate (PIP2) synthesis, providing extra substrate for preactivated PLC-β to generate inositol 1,4,5-trisphosphate (IP3). Somatostatin alone did not increase IP3 levels, but AVP + somatostatin did. Somatostatin increased PIP2 levels but decreased phosphatidylinositol 4-phosphate levels. We further hypothesized that PLD mediates somatostatin-induced changes in PIP2 levels. Both the phospholipase D (PLD) inhibitors and antibody versus PLD1 antagonized AVP-somatostatin-induced increases in [Ca2+]i. PLD inhibitor also antagonized somatostatin-induced increase in PIP2 levels. In addition, somatostatin increased PLD activity. These results suggest that activation of somatostatin receptors that are coupled to the βγ dimer of Gi/o led to PLD1 activation, thus promoting the synthesis of phosphatidic acid. Phosphatidic acid activates PIP-5 kinase, which evokes an increase in PIP2 synthesis. The PIP2 generated by somatostatin administration increases substrate for preactivated phospholipase C-β, which hydrolyzes PIP2 to form IP3, leading to an increase in [Ca2+]i. The regulation of PIP2 synthesis by Gi/o-coupled receptors via PLD activation represents a novel signaling mechanism for somatostatin and a novel concept in the cross-talk between Gq- and Gi/o-coupled receptors in β cells. ER -