Triheteromeric GluN1/GluN2A/GluN2C NMDARs with Unique Single-Channel Properties Are the Dominant Receptor Population in Cerebellar Granule Cells

• Type of Material: Article
• Authors: Subhrajit Bhattacharya, Emory University; Alpa Khatri, Emory University; Sharon Swanger, Emory University; John O. DiRaddo, Emory University; Feng Yi, University of Montana; Kasper B. Hansen, University of Montana; Hongjie Yuan, Emory University; Stephen Traynelis, Emory University
• Language: English
• Date: 2018-07-25
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc. CC BY NC ND 4.0
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuron.2018.06.010
• Title of Journal or Parent Work: Neuron
• ISSN: 0896-6273
• Volume: 99
• Issue: 2
• Start Page: 315
• End Page: +
• Grant/Funding Information: This work was supported by the NIH (NS036654 and NS065371 to S.F.T., GM103546 and NS097536 to K.B.H., NS086361 to S.A.S., and NS078873 to A.K).
• Keywords: Life Sciences & Biomedicine; SUBUNIT MESSENGER-RNAS; Neurosciences; DIFFERENTIAL EXPRESSION; STRUCTURAL DETERMINANTS; GABA(B) RECEPTOR; Neurosciences & Neurology; CEREBRAL-CORTEX; D-CYCLOSERINE; PARTIAL AGONIST; Science & Technology; D-ASPARTATE RECEPTORS; MOLECULAR-BASIS; AFFINITY ZINC INHIBITION
• Research Categories: Health Sciences, Pharmacology

Abstract

NMDA-type glutamate receptors (NMDARs) are ligand-gated ion channels that mediate excitatory neurotransmission in the CNS. Here we describe functional and single-channel properties of triheteromeric GluN1/GluN2A/GluN2C receptors, which contain two GluN1, one GluN2A, and one GluN2C subunits. This NMDAR has three conductance levels and opens in bursts similar to GluN1/GluN2A receptors but with a single-channel open time and open probability reminiscent of GluN1/GluN2C receptors. The deactivation time course of GluN1/GluN2A/GluN2C receptors is intermediate to GluN1/GluN2A and GluN1/GluN2C receptors and is not dominated by GluN2A or GluN2C. We show that triheteromeric GluN1/GluN2A/GluN2C receptors are the predominant NMDARs in cerebellar granule cells and propose that co-expression of GluN2A and GluN2C in cerebellar granule cells occludes cell surface expression of diheteromeric GluN1/GluN2C receptors. This new insight into neuronal GluN1/GluN2A/GluN2C receptors highlights the complexity of NMDAR signaling in the CNS. Bhattacharya et al. show that the NMDA receptor GluN2C subunit is preferentially incorporated into triheteromeric GluN1/GluN2A/GluN2C receptors in cerebellar granule cells. Triheteromeric GluN1/GluN2A/GluN2C receptors have single-channel properties that cannot be predicted from the composite subunits.