Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors

Johannes J. Krupp; Bryce Vissel; Christopher G. Thomas; Stephen F. Heinemann; Gary L. Westbrook

doi:10.1016/S0028-3908(02)00031-X

Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors

Johannes J. Krupp, Bryce Vissel, Christopher G. Thomas, Stephen F. Heinemann, Gary L. Westbrook

Vollum Institute

Research output: Contribution to journal › Article › peer-review

92 Scopus citations

Abstract

Phosphatase IIb (calcineurin, CaN) can reduce N-methyl-D-aspartate (NMDA) synaptic responses by enhancing glycine-independent desensitization. We examined the action of CaN on desensitization in recombinant NMDA receptors comprised of NMDA receptor 1 (NR1) and NR2A subunits. The C-terminus of NR2A, but not NR1, was critical for modulation of desensitization by CaN. Alanine-scanning mutagenesis indicated that serines 900 and 929 in NR2A altered desensitization, as did inhibition of tyrosine phosphatases. Our data suggest that dephosphorylation-dependent regulation of the C-terminus of NR2A increases desensitization of NMDA receptors, providing an additional mechanism for modulation of synaptic signals.

Original language	English (US)
Pages (from-to)	593-602
Number of pages	10
Journal	Neuropharmacology
Volume	42
Issue number	5
DOIs	https://doi.org/10.1016/S0028-3908(02)00031-X
State	Published - 2002

Keywords

Calcineurin
Desensitization
Mutagenesis
NMDA receptors
Patch-clamp
Tyrosine phosphatases

ASJC Scopus subject areas

Pharmacology
Cellular and Molecular Neuroscience

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10.1016/S0028-3908(02)00031-X

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title = "Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors",

abstract = "Phosphatase IIb (calcineurin, CaN) can reduce N-methyl-D-aspartate (NMDA) synaptic responses by enhancing glycine-independent desensitization. We examined the action of CaN on desensitization in recombinant NMDA receptors comprised of NMDA receptor 1 (NR1) and NR2A subunits. The C-terminus of NR2A, but not NR1, was critical for modulation of desensitization by CaN. Alanine-scanning mutagenesis indicated that serines 900 and 929 in NR2A altered desensitization, as did inhibition of tyrosine phosphatases. Our data suggest that dephosphorylation-dependent regulation of the C-terminus of NR2A increases desensitization of NMDA receptors, providing an additional mechanism for modulation of synaptic signals.",

keywords = "Calcineurin, Desensitization, Mutagenesis, NMDA receptors, Patch-clamp, Tyrosine phosphatases",

author = "Krupp, {Johannes J.} and Bryce Vissel and Thomas, {Christopher G.} and Heinemann, {Stephen F.} and Westbrook, {Gary L.}",

note = "Funding Information: This work was supported by NIH grants MH46613 (GLW), NS28709 (SFH), the McKnight Foundation (SFH), the Hereditary Disease Foundation Lieberman Award (BV), the John Adler Foundation (SFH), fellowships from the Human Frontiers program (JJK and BV), a Bundy Foundation award (BV), and a CJ Martin NHMRC of Australia award (BV).",

year = "2002",

doi = "10.1016/S0028-3908(02)00031-X",

language = "English (US)",

volume = "42",

pages = "593--602",

journal = "Neuropharmacology",

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T1 - Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors

AU - Krupp, Johannes J.

AU - Vissel, Bryce

AU - Thomas, Christopher G.

AU - Heinemann, Stephen F.

AU - Westbrook, Gary L.

N1 - Funding Information: This work was supported by NIH grants MH46613 (GLW), NS28709 (SFH), the McKnight Foundation (SFH), the Hereditary Disease Foundation Lieberman Award (BV), the John Adler Foundation (SFH), fellowships from the Human Frontiers program (JJK and BV), a Bundy Foundation award (BV), and a CJ Martin NHMRC of Australia award (BV).

PY - 2002

Y1 - 2002

N2 - Phosphatase IIb (calcineurin, CaN) can reduce N-methyl-D-aspartate (NMDA) synaptic responses by enhancing glycine-independent desensitization. We examined the action of CaN on desensitization in recombinant NMDA receptors comprised of NMDA receptor 1 (NR1) and NR2A subunits. The C-terminus of NR2A, but not NR1, was critical for modulation of desensitization by CaN. Alanine-scanning mutagenesis indicated that serines 900 and 929 in NR2A altered desensitization, as did inhibition of tyrosine phosphatases. Our data suggest that dephosphorylation-dependent regulation of the C-terminus of NR2A increases desensitization of NMDA receptors, providing an additional mechanism for modulation of synaptic signals.

AB - Phosphatase IIb (calcineurin, CaN) can reduce N-methyl-D-aspartate (NMDA) synaptic responses by enhancing glycine-independent desensitization. We examined the action of CaN on desensitization in recombinant NMDA receptors comprised of NMDA receptor 1 (NR1) and NR2A subunits. The C-terminus of NR2A, but not NR1, was critical for modulation of desensitization by CaN. Alanine-scanning mutagenesis indicated that serines 900 and 929 in NR2A altered desensitization, as did inhibition of tyrosine phosphatases. Our data suggest that dephosphorylation-dependent regulation of the C-terminus of NR2A increases desensitization of NMDA receptors, providing an additional mechanism for modulation of synaptic signals.

KW - Calcineurin

KW - Desensitization

KW - Mutagenesis

KW - NMDA receptors

KW - Patch-clamp

KW - Tyrosine phosphatases

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SN - 0028-3908

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JO - Neuropharmacology

JF - Neuropharmacology

IS - 5

ER -

Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors

Abstract

Keywords

ASJC Scopus subject areas

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