Insulin Promotes Rapid Delivery of N-Methyl-D-Aspartate Receptors to the Cell Surface by Exocytosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 6; pp. 3561 - 3566
• Main Authors: Skeberdis, Vytenis A., Lan, Jian-yu, Zheng, Xin, Zukin, R. Suzanne, Michael V. L. Bennett
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.03.2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Animals; Biological Sciences; Biological Transport; Cell Membrane - metabolism; Cell Membrane - physiology; Cell membranes; Electric Conductivity; Electric current; Electrophysiology; Enzyme Activation; Exocytosis; Exocytosis - physiology; Female; Gene Expression; Insulin; Insulin - metabolism; Insulin - pharmacology; Ion Channel Gating - physiology; Membrane proteins; Mice; Neurology; Neurons; Neuroscience; Oocytes; Oocytes - metabolism; Patch-Clamp Techniques; Phosphorylation; Rats; Receptor, Insulin - metabolism; Receptors; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Receptors, N-Methyl-D-Aspartate - physiology; Time Factors; Tyrosine - metabolism; Xenopus laevis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.051634698

Insulin potentiates N-methyl-D-aspartate receptors (NMDARs) in neurons and Xenopus oocytes expressing recombinant NMDARs. The present study shows that insulin induced (i) an increase in channel number times open probability (nPo) in outside-out patches excised from Xenopus oocytes, with no change in mean open time, unitary conductance, or reversal potential, indicating an increase in n and/or Po; (ii) an increase in charge transfer during block of NMDA-elicited currents by the open channel blocker MK-801, indicating increased number of functional NMDARs in the cell membrane with no change in P o; and (iii) increased NR1 surface expression, as indicated by Western blot analysis of surface proteins. Botulinum neurotoxin A greatly reduced insulin potentiation, indicating that insertion of new receptors occurs via SNARE-dependent exocytosis. Thus, insulin potentiation occurs via delivery of new channels to the plasma membrane. NMDARs assembled from mutant subunits lacking all known sites of tyrosine and serine/threonine phosphorylation in their carboxyl-terminal tails exhibited robust insulin potentiation, suggesting that insulin potentiation does not require direct phosphorylation of NMDAR subunits. Because insulin and insulin receptors are localized to glutamatergic synapses in the hippocampus, insulin-regulated trafficking of NMDARs may play a role in synaptic transmission and plasticity, including long-term potentiation.