Triphenyltin impairs a protein kinase A (PKA)-dependent increase of cytosolic Na(+) and Ca(2+) and PKA-independent increase of cytosolic Ca(2+) associated with insulin secretion in hamster pancreatic beta-cells.
Oral administration of triphenyltin chloride (TPT) (60 mg/kg body weight) inhibits the insulin secretion by decreasing the cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) induced by glucose-dependent insulinotropic polypeptide (GIP) in pancreatic beta-cells of the hamster. To test the possibility that the abnormal level of [Ca(2+)](i) induced by TPT administration could be due to a defect in the cAMP-dependent cytoplasmic Na(+) concentration ([Na(+)](i)) in the beta-cells, we investigated the effects of TPT administration on the changes of [Na(+)](i) induced by GIP, glucagon-like peptide-1 (GLP-1), or forskolin, an activator of adenylyl cyclase, and on the changes of [Na(+)](i) or [Ca(2+)](i) induced by 6-Bnz-cAMP, an activator of protein kinase A (PKA), and 8-pCPT-2'-O-Me-cAMP, an activator of Epac. The [Na(+)](i) and [Ca(2+)](i) were measured in islet cells loaded with sodium-binding benzofuran isophthalate (SBFI) and fura-2, respectively. In the presence of 135 mM Na(+), TPT administration significantly reduced the rise in [Na(+)](i) by 10 nM GLP-1, 10 muM forskolin, and 50 muM 6-Bnz-cAMP, but had not effect in a Na(+)-free medium. In the presence of 135 mM Na(+), TPT administration also reduced the rise in [Ca(2+)](i) by 8-pCPT-2'-O-Me-cAMP plus10 muM H-89, a inhibitor of PKA, and 6-Bnz-cAMP. Moreover, TPT administration significantly reduced the insulin secretion by 2 mM db-cAMP, GLP-1, GIP, and 8-pCPT-2'-O-Me-cAMP with and without H-89, and that by 6-Bnz-cAMP and forskolin. Our study suggested that TPT has inhibitory effects on the cellular Ca(2+) response due to a reduced Na(+) permeability through PKA-dependent mechanisms in hamster islet cells. Also TPT has the reduction of [Ca(2+)](i) related to Na(+)-dependent insulin secretion after an activation of Epac.[1]References
- Triphenyltin impairs a protein kinase A (PKA)-dependent increase of cytosolic Na(+) and Ca(2+) and PKA-independent increase of cytosolic Ca(2+) associated with insulin secretion in hamster pancreatic beta-cells. Miura, Y., Matsui, H. Toxicol. Appl. Pharmacol. (2006) [Pubmed]
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