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Somatostatin Increases Phospholipase D Activity and Phosphatidylinositol 4,5-bisphosphate Synthesis in Clonal Cells HIT-T15

Department of Biomedical Sciences, Iowa State University, Ames, Iowa

In the presence of arginine vasopressin (AVP), somatostatin increases [Ca²⁺]_i, leading to a transient increase in insulin release from clonal 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 [Ca²⁺]_i increase in the presence of AVP. We found that the effect of somatostatin was mediated by subunits but not by the subunit of G_i/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- 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 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 PIP₂ synthesis. The PIP₂ generated by somatostatin administration increases substrate for preactivated phospholipase C-, which hydrolyzes PIP₂ to form IP₃, leading to an increase in [Ca²⁺]_i. The regulation of PIP₂ 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 cells.

Address correspondence to: Dr. Walter H. Hsu, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011-1250. E-mail: whsu{at}iastate.edu

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				J. A. Grodnitzky, N. Syed, M. J. Kimber, T. A. Day, J. G. Donaldson, and W. H. Hsu Somatostatin Receptors Signal through EFA6A-ARF6 to Activate Phospholipase D in Clonal beta-Cells J. Biol. Chem., May 4, 2007; 282(18): 13410 - 13418. [Abstract] [Full Text] [PDF]