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 β-cells
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 β-cells
复制标题
DOI：
10.1016/j.taap.2006.05.017
复制
发表时间：
2006-11-01
影响因子：
3.8
通讯作者：
Matsui, Hisao
中科院分区：
文献类型：
--
作者：
Miura, Yoshikazu;Matsui, Hisao
经口给予三苯基氯化锡（TPT）（60 mg/kg体重）通过降低仓鼠胰腺β细胞中葡萄糖依赖性促胰岛素多肽（GIP）诱导的细胞质Ca 2+浓度（[Ca 2 +]（i））抑制胰岛素分泌。为了测试TPT给药诱导的[Ca 2 +]（i）异常水平可能是由于β细胞中cAMP依赖性细胞质Na+浓度（[Na+]（i））缺陷所致的可能性，我们研究了TPT给药对GIP、胰高血糖素样肽-1（GLP-1）或腺苷酸环化酶激活剂毛喉素诱导的[Na+]（i）变化的影响，对蛋白激酶A（PKA）激活剂6-Bnz-cAMP和Epac激活剂8-pCPT-2 ′-O-Me-cAMP引起的[Na+]（i）和[Ca ~（2+）]（i）的变化也有影响。在分别负载钠结合苯并呋喃二甲酸酯（SBFI）和fura-2的胰岛细胞中测量[Na+]（i）和[Ca 2 +]（i）。在存在135 mM Na+的情况下，TPT给药显著降低了10 nM GLP-1、10 μ M毛喉素和50 μ M 6-Bnz-cAMP引起的[Na+]（i）升高，但在无Na+的培养基中没有影响。在135 mM Na+存在下，TPT给药也减少8-pCPT-2 ′-O-Me-cAMP加10 μ M H-89（PKA抑制剂）和6-Bnz-cAMP引起的[Ca ~（2+）]（i）升高。此外，TPT给药显著降低了2 mM db-cAMP、GLP-1、GIP和8-pCPT-2 '-O-Me-cAMP（含和不含H-89）以及6-Bnz-cAMP和毛喉素的胰岛素分泌。我们的研究表明，TPT具有抑制作用的细胞Ca 2+的反应，由于通过PKA依赖的机制，在仓鼠胰岛细胞的Na+渗透性降低。TPT还具有与Epac激活后的Na+依赖性胰岛素分泌相关的[Ca 2 +]（i）的减少。(c)2006爱思唯尔公司All rights reserved.
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 mu M forskolin, and 50 mu M 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 mu M 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. (c) 2006 Elsevier Inc. All rights reserved.