Abstract
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.
- Received December 19, 2004.
- Accepted March 22, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|