Alteration of Ca2+ permeability and sensitivity to Mg2+ and channel blockers by a single amino acid substitution in the N-methyl-D-aspartate receptor

K. Sakurada, M. Masu, S. Nakanishi

Research output: Contribution to journalArticlepeer-review

139 Citations (Scopus)

Abstract

The N-methyl-D-aspartate (NMDA) receptor plays an important role in glutamate-mediated neuronal plasticity and neurotoxicity in the central nervous system. This receptor is composed of a fundamental subunit (NMDAR1) and its potentiating subunits (NMDAR2A-NMDAR2D). The NMDA receptor is distinct from other glutamate receptor channels because of its high Ca2+ permeability and inhibition by selective cationic channel blockers such as Mg2+, Zn2+, and MK-801. In this study, we investigated the structural features that control Ca2+ permeation and channel blockade of the NMDA receptor by in vitro mutagenesis and expression in Xenopus oocytes. We constructed a series of mutations with single amino acid substitutions in the second transmembrane segment of NMDAR1 and examined channel properties of the resultant mutants in combined expression with the NMDAR2A subunit. Substitution of the asparagine with either glutamine or arginine altered both the Ca2+ permeability and the sensitivity to blockades by Mg2+ and MK- 801. These mutations also reduced the inhibitory effects of Zn2+ and an antidepressant, desipramine. Based on these results, we concluded that an asparagine ring formed in the central part of the channel-forming second transmembrane segments plays a critical role in determining the Ca2+ permeability and the inhibition of open channel blockers.

Original languageEnglish
Pages (from-to)410-415
Number of pages6
JournalJournal of Biological Chemistry
Volume268
Issue number1
Publication statusPublished - 1993
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Alteration of Ca<sup>2+</sup> permeability and sensitivity to Mg<sup>2+</sup> and channel blockers by a single amino acid substitution in the N-methyl-D-aspartate receptor'. Together they form a unique fingerprint.

Cite this