NMDA receptors mediate leptin signaling and regulate potassium channel trafficking in pancreatic Β-cells

Yi Wu, Dale A. Fortin, Veronica A. Cochrane, Pei Chun Chen, Show Ling Shyng

研究成果: Article同行評審

28 引文 斯高帕斯(Scopus)

摘要

NMDA receptors (NMDARs) are Ca2-permeant, ligand-gated ion channels activated by the excitatory neurotransmitter glutamate and have well-characterized roles in the nervous system. The expression and function of NMDARs in pancreatic -cells, by contrast, are poorly understood. Here, we report a novel function of NMDARs in -cells. Using a combination of biochemistry, electrophysiology, and imaging techniques, we now show that NMDARs have a key role in mediating the effect of leptin to modulate -cell electrical activity by promoting AMP-activated protein kinase (AMPK)-dependent trafficking of KATP and Kv2.1 channels to the plasma membrane. Blocking NMDAR activity inhibited the ability of leptin to activate AMPK, induce KATP and Kv2.1 channel trafficking, and promote membrane hyperpolarization. Conversely, activation of NMDARs mimicked the effect of leptin, causing Ca2 influx, AMPK activation, and increased trafficking of KATP and Kv2.1 channels to the plasma membrane, and triggered membrane hyperpolarization. Moreover, leptin potentiated NMDAR currents and triggered NMDAR-dependent Ca2 influx. Importantly, NMDAR-mediated signaling was observed in rat insulinoma 832/13 cells and in human -cells, indicating that this pathway is conserved across species. The ability of NMDARs to regulate potassium channel surface expression and thus, -cell excitability provides mechanistic insight into the recently reported insulinotropic effects of NMDAR antagonists and therefore highlights the therapeutic potential of these drugs in managing type 2 diabetes.

原文English
頁(從 - 到)15512-15524
頁數13
期刊Journal of Biological Chemistry
292
發行號37
DOIs
出版狀態Published - 2017 9月 15

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 分子生物學
  • 細胞生物學

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