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

• 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
• Journal Title: Neuron
• Volume: Volume 99, Number 2
• Publisher: Elsevier (Cell Press): 12 month embargo | 2018-07-25, Pages 315-+
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.neuron.2018.06.010
• Subjects: Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; SUBUNIT MESSENGER-RNAS; AFFINITY ZINC INHIBITION; D-ASPARTATE RECEPTORS; PARTIAL AGONIST; DIFFERENTIAL EXPRESSION; STRUCTURAL DETERMINANTS; D-CYCLOSERINE; GABA(B) RECEPTOR; CEREBRAL-CORTEX; MOLECULAR-BASIS

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.