title: Somatostatin increases phospholipase D activity and phosphatidylinositol 4,5-bisphosphate synthesis in clonal beta cells HIT-T15.
abstract: In the presence of arginine vasopressin (AVP), somatostatin increases [Ca(2+)](i), leading to a transient increase in insulin release from clonal beta cells HIT-T15 via G(i/o) and phospholipase C (PLC) pathway (Cheng et al., 2002a). The present study was to elucidate the mechanisms underlying somatostatin-induced [Ca(2+)](i) increase in the presence of AVP. We found that the effect of somatostatin was mediated by betagamma subunits but not by the alpha subunit of G(i/o). Because somatostatin alone failed to increase [Ca(2+)](i), we hypothesized that somatostatin increases phosphatidylinositol 4,5-bisphosphate (PIP(2)) synthesis, providing extra substrate for preactivated PLC-beta to generate inositol 1,4,5-trisphosphate (IP(3)). Somatostatin alone did not increase IP(3) levels, but AVP + somatostatin did. Somatostatin increased PIP(2) levels but decreased phosphatidylinositol 4-phosphate levels. We further hypothesized that PLD mediates somatostatin-induced changes in PIP(2) levels. Both the phospholipase D (PLD) inhibitors and antibody versus PLD1 antagonized AVP-somatostatin-induced increases in [Ca(2+)](i). PLD inhibitor also antagonized somatostatin-induced increase in PIP(2) levels. In addition, somatostatin increased PLD activity. These results suggest that activation of somatostatin receptors that are coupled to the betagamma dimer of G(i/o) led to PLD1 activation, thus promoting the synthesis of phosphatidic acid. Phosphatidic acid activates PIP-5 kinase, which evokes an increase in PIP(2) synthesis. The PIP(2) generated by somatostatin administration increases substrate for preactivated phospholipase C-beta, which hydrolyzes PIP(2) to form IP(3), leading to an increase in [Ca(2+)](i). The regulation of PIP(2) synthesis by G(i/o)-coupled receptors via PLD activation represents a novel signaling mechanism for somatostatin and a novel concept in the cross-talk between G(q)- and G(i/o)-coupled receptors in beta cells.
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA 50011-1250, USA.
authors.forename: Henrique
authors.initials: H
authors.lastname: Cheng
authors.forename: Justin A
authors.initials: JA
authors.lastname: Grodnitzky
authors.forename: Sirintorn
authors.initials: S
authors.lastname: Yibchok-anun
authors.forename: Jing
authors.initials: J
authors.lastname: Ding
authors.forename: Walter H
authors.initials: WH
authors.lastname: Hsu
mesh_terms: D000818:Animals; D002999:Clone Cells; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000096:biosynthesis*; D010739:Phospholipase D / Q000378:metabolism*; D013004:Somatostatin / Q000494:pharmacology* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D013004:Somatostatin; D010739:Phospholipase D