Triphenyltin impairs a protein kinase A (PKA)-dependent increase of cytosolic Na+ and Ca2+ and PKA-independent increase of cytosolic Ca2+ 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 Ca2+ concentration ([Ca2+]i) induced by glucose-dependent insulinotropic polypeptide (GIP) in pancreatic beta-cells of the hamster. To test the possibility that the abnormal level of [Ca2+]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 [Ca2+]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 [Ca2+]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 microM forskolin, and 50 microM 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 [Ca2+]i by 8-pCPT-2'-O-Me-cAMP plus10 microM 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 Ca2+ response due to a reduced Na+ permeability through PKA-dependent mechanisms in hamster islet cells. Also TPT has the reduction of [Ca2+]i related to Na+-dependent insulin secretion after an activation of Epac.
Miura
Yoshikazu
Y
Department of Hygiene, Dokkyo Medical University School of Medicine, 880 Mibu, Tochigi 321-0293, Japan. y-miura@dokkyomed.ac.jp
Matsui
Hisao
H
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism*; D004785:Environmental Pollutants / Q000633:toxicity*; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D009947:Organotin Compounds / Q000633:toxicity*; D012964:Sodium / Q000378:metabolism*
D004785:Environmental Pollutants; D007328:Insulin; D009947:Organotin Compounds; D005576:Colforsin; D005749:Gastric Inhibitory Polypeptide; D003994:Bucladesine; D052216:Glucagon-Like Peptide 1; C030665:triphenyltin; D012964:Sodium; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium