TRPM4 controls insulin secretion in pancreatic β-cells
TRPM4 controls insulin secretion in pancreatic β-cells
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DOI：
10.1016/j.ceca.2006.04.032
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发表时间：
2007-01-01
期刊：
影响因子：
4
通讯作者：
Penner, Reinhold
中科院分区：
文献类型：
--
作者：
Cheng, Henrique;Beck, Andreas;Penner, Reinhold
TRPM4是一种钙激活的非选择性阳离子通道，广泛表达，并被认为参与细胞去极化。在可兴奋细胞中，TRPM4可能通过引起电压依赖性钙通道的去极化来调节钙内流。本文报道大鼠胰岛β细胞系INS的胰岛素分泌细胞天然表达TRPM4蛋白，并对细胞内钙离子升高产生大的去极化膜电流。这些电流表现出TRPM4的特征，并且可以通过表达显性的负TRPM4结构来抑制，导致对葡萄糖刺激的胰岛素分泌显著减少。精氨酸加压素刺激P细胞上的GQ偶联受体激动剂也可观察到胰岛素分泌减少。此外，在高表达TRPM4的INS-1细胞和HEK-293细胞中，TRPM4电流的募集都是双相的。第一阶段是由于位于质膜内的TRPM4通道的激活，随后是较慢的第二阶段，这是由于胞吐过程中含有TRPM4的囊泡重新聚集到质膜所致。在细胞灌流过程中，随着[Ca~(2+)](I)的升高，在激动剂的刺激下，可以观察到第二相，与细胞电容的增加、FM1-43染料的丢失和囊泡融合相一致。我们的数据表明，TRPM4可能在电刺激分泌细胞的膜电位和电活动的控制中起关键作用，TRPM4通过钙离子依赖的胞吐作用从囊泡池动态转移到质膜可能是细胞调节电活动的一个关键的中短期调节机制。(C)2006爱思唯尔有限公司。保留所有权利。
TRPM4 is a calcium-activated non-selective cation channel that is widely expressed and proposed to be involved in cell depolarization. In excitable cells, TRPM4 may regulate calcium influx by causing the depolarization that drives the activation of voltage-dependent calcium channels. We here report that insulin-secreting cells of the rat pancreatic beta-cell line INS-I natively express TRPM4 proteins and generate large depolarizing membrane currents in response to increased intracellular calcium. These currents exhibit the characteristics of TRPM4 and can be suppressed by expressing a dominant negative TRPM4 construct, resulting in significantly decreased insulin secretion in response to a glucose stimulus. Reduced insulin secretion was also observed with arginine vasopressin stimulation, a Gq-coupled receptor agonist in P-cells. Moreover, the recruitment of TRPM4 currents was biphasic in both INS-1 cells as well as HEK-293 cells overexpressing TRPM4. The first phase is due to activation of TRPM4 channels localized within the plasma membrane followed by a slower secondary phase, which is caused by the recruitment of TRPM4-containing vesicles to the plasma membrane during exocytosis. The secondary phase can be observed during perfusion of cells with increasing [Ca2+](i), replicated with agonist stimulation, and coincides with an increase in cell capacitance, loss of FM1-43 dye, and vesicle fusion. Our data suggest that TRPM4 may play a key role in the control of membrane potential and electrical activity of electrically excitable secretory cells and the dynamic translocation of TRPM4 from a vesicular pool to the plasma membrane via Ca2+-dependent exocytosis may represent a key short- and midterm regulatory mechanism by which cells regulate electrical activity. (c) 2006 Elsevier Ltd. All rights reserved.