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Research ArticleArticle

Intracellular Domains of NR2 Alter Calcium-Dependent Inactivation of N-Methyl-d-aspartate Receptors

Bryce Vissel, Johannes J. Krupp, Stephen F. Heinemann and Gary L. Westbrook
Molecular Pharmacology March 2002, 61 (3) 595-605; DOI: https://doi.org/10.1124/mol.61.3.595
Bryce Vissel
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Johannes J. Krupp
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Stephen F. Heinemann
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Gary L. Westbrook
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Abstract

At central excitatory synapses, the transient elevation of intracellular calcium reducesN-methyl-d-aspartate (NMDA) receptor activity. Such ‘calcium-dependent inactivation’ is mediated by interactions of calcium/calmodulin and α-actinin with the C terminus of NMDA receptor 1 (NR1) subunit. However, inactivation is also NR2-subunit specific, because it occurs in NR2A- but not NR2C-containing receptors. We examined the molecular basis for NR2-subunit specificity using chimeric and mutated NMDA receptor subunits expressed in HEK293 cells. We report that the intracellular loop immediately distal to the pore-forming P-loop M2 (M2–3 loop), as well as a short region in the C terminus, are involved in NR2-subunit specificity. Within the M2–3 loop, substitution of residue 619 in NR2A (valine) for the corresponding NR2C residue (isoleucine) reduced inactivation without affecting calcium permeability of the channel. In contrast, a Q620E mutation in NR2A reduced the relative calcium permeability without altering inactivation. Mutation of three serine/threonine residues in the M2–3 loop also reduced inactivation, as did substitution of the intracellular C terminus of NR2A for NR2C. We speculate that the M2–3 loop of NR2 modulates calcium-dependent inactivation by interacting with the NR1 C terminus, a region known to be essential for inactivation.

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Molecular Pharmacology: 61 (3)
Molecular Pharmacology
Vol. 61, Issue 3
1 Mar 2002
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Research ArticleArticle

Intracellular Domains of NR2 Alter Calcium-Dependent Inactivation of N-Methyl-d-aspartate Receptors

Bryce Vissel, Johannes J. Krupp, Stephen F. Heinemann and Gary L. Westbrook
Molecular Pharmacology March 1, 2002, 61 (3) 595-605; DOI: https://doi.org/10.1124/mol.61.3.595

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Research ArticleArticle

Intracellular Domains of NR2 Alter Calcium-Dependent Inactivation of N-Methyl-d-aspartate Receptors

Bryce Vissel, Johannes J. Krupp, Stephen F. Heinemann and Gary L. Westbrook
Molecular Pharmacology March 1, 2002, 61 (3) 595-605; DOI: https://doi.org/10.1124/mol.61.3.595
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