TY - JOUR
T1 - NMDA receptors mediate leptin signaling and regulate potassium channel trafficking in pancreatic Β-cells
AU - Wu, Yi
AU - Fortin, Dale A.
AU - Cochrane, Veronica A.
AU - Chen, Pei Chun
AU - Shyng, Show Ling
N1 - Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/9/15
Y1 - 2017/9/15
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M117.802249
DO - 10.1074/jbc.M117.802249
M3 - Article
C2 - 28768770
AN - SCOPUS:85029530260
SN - 0021-9258
VL - 292
SP - 15512
EP - 15524
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -