Abstract
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 β-cells, by contrast, are poorly understood. Here, we report a novel function of NMDARs in β-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 β-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 β-cells, indicating that this pathway is conserved across species. The ability of NMDARs to regulate potassium channel surface expression and thus, β-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.
Highlights
NMDA receptors (NMDARs) are Ca2؉-permeant, ligandgated ion channels activated by the excitatory neurotransmitter glutamate and have well-characterized roles in the nervous system
Using a combination of biochemistry, electrophysiology, and imaging techniques, we 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
We first determined whether NMDARs are expressed by INS-832/13 cells, which were used in our previous studies
Summary
We previously reported that leptin increases the surface density of KATP and Kv2.1 channels in rat insulinoma INS-832/13 cells and human -cells. Puff application of glutamate (1 mM), a physiological ligand of the NMDAR, elicited outward currents when cells were held at a positive potential of 40 mV that were reversibly blocked by MK-801 (27.8 Ϯ 7.0 pA for glutamate, 2.3 Ϯ 1.4 pA for MK-801, and 23.5 Ϯ 6.7 pA for MK-801 washout; p Ͻ 0.01, n ϭ 5 by paired t test; Fig. 1G) Together, these results show that both INS-832/13 cells and human -cells express functional NMDARs. NMDARs are required for leptin-induced surface trafficking of KATP and Kv2.1 channels. These data reveal a novel link between leptin signaling and the function of NMDARs in -cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
