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

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

doi:10.1016/s0028-3908(02)00031-x

Cited by 98 publications

(108 citation statements)

References 46 publications

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“…However, recent evidence has implicated phosphorylation of the cytoplasmic C terminal of the NR2A subunit in this desensitization. Ser900 of NR2A was of particular interest, because it can be dephosphorylated by CaN, and mutation to alanine induces a persistently desensitized state (Krupp et al, 2002). Desensitization could be consistent with the faster NMDAR current decay time seen in the sSC after CaN activation.…”

Section: Discussionmentioning

confidence: 99%

“…Such desensitization, if prolonged, could constitute the mechanism underlying the developmental downregulation of NMDAR decay time in vivo. Krupp et al (2002) recently identified Ser900 on the NR2A subunit as a phosphorylation site regulated by CaN. This site, when mutated to alanine, caused a persistent glycineindependent desensitization that was normally only seen after agonist was repetitively applied to human embryonic kidney 293 cells transfected with NR1 and the NR2A containing Ser900.…”

Section: Nr2a Dephosphorylation At Ser900 Coincides With Canmediated mentioning

confidence: 99%

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Retina-Driven Dephosphorylation of the NR2A Subunit Correlates with Faster NMDA Receptor Kinetics at Developing Retinocollicular Synapses

Townsend¹,

Liu²,

Constantine‐Paton³

2004

J. Neurosci.

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We describe a homeostatic mechanism that limits NMDA receptor currents in response to early light activation of a developing visual pathway. During the second postnatal week of rodent retinocollicular development, the Ca 2ϩ -activated phosphatase calcineurin (CaN) mediates a rapid, activity-induced shortening in the decay time of NMDA receptor (NMDAR) currents. We show that protein kinase A acts in opposition to CaN to maintain NMDAR currents with long decay times. The CaN-mediated change is coincident with the initial expression of the NMDAR subunit NR2A. Using NR2A knock-out mice and dialyzing neurons with a constitutively active CaN, we demonstrate that NR2A subunits are necessary for the effect of CaN on NMDAR current kinetics. In wild-type mice, Ser900 of NR2A, previously implicated in CaN-mediated glycine-independent desensitization, becomes chronically dephosphorylated by postnatal day 11 as NMDAR current decay times become faster. Pharmacologically disrupting early photoreceptor-driven activity in the retina eliminates the dephosphorylation of NR2A and prevents the shortening in NMDAR current decay time. These data suggest that the developmental onset of retinal activity increases CaN-mediated dephosphorylation of NR2A subunits newly incorporated into synaptic NMDARs of the superior colliculus, thereby providing a mechanism for the early and rapid reduction of NMDAR current decay time in visual neurons.

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Section: Discussionmentioning

confidence: 99%

Section: Nr2a Dephosphorylation At Ser900 Coincides With Canmediated mentioning

confidence: 99%

Retina-Driven Dephosphorylation of the NR2A Subunit Correlates with Faster NMDA Receptor Kinetics at Developing Retinocollicular Synapses

Townsend¹,

Liu²,

Constantine‐Paton³

2004

J. Neurosci.

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“…In addition, repeated administration of METH reduces immunoreactivities of NR1 and NMDA receptors comprising NMDA receptor 2A and 2B in the striatum [26]. Continuous stimulation of NMDA receptors induces desensitization of this type of receptor [13,14]. Considering these findings, the repeated administration of METH 2.5 mg/kg might desensitize NMDA receptors, thereby inducing hypersensitivity to MK-801.…”

Section: Discussionmentioning

confidence: 98%

Lamotrigine blocks repeated high-dose methamphetamine-induced behavioral sensitization to dizocilpine (MK-801), but not methamphetamine in rats

Nakato

Abekawa

Inoue

et al. 2011

Neuroscience Letters

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“…Thus, it is not surprising that synaptic efficacy can be reduced by many different mechanisms including downregulation of postsynaptic receptors (Krupp et al, 2002). On a time scale of minutes such downregulation can involve endocytosis of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors that are also a subtype of ionotropic Glu receptors (Man et al, 2000;Lin et al, 2000;Ehlers, 2001), and possibly also for NMDA receptors (Roche et al, 2001;Vissel et al, 2001;Nong et al, 2003Nong et al, , 2004.…”

Section: +mentioning

confidence: 99%

“…On the timescale of seconds and milliseconds receptor desensitization can inhibit synaptic transmission (Trussell and Fischbach, 1989;Trussell et al, 1993;Tong et al, 1995). Desensitization is particularly important in shaping single synaptic events and the integration of high-frequency inputs during sustained firings (Trussell and Fischbach, 1989;Jones and Westbrook, 1996;Krupp et al, 2002).…”

Section: +mentioning

confidence: 99%

Maturation-dependent reduced responsiveness of intracellular free Ca2+ ions to repeated stimulation by N-methyl-d-aspartate in cultured rat cortical neurons

Nakamichi

Yoneda

2006

Neurochemistry International

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In contrast to other ionotropic glutamate receptors, N-methyl-D-aspartate (NMDA) receptor channels are rather stable after the simulation. Brief exposure to NMDA at 50 µM rapidly increased the fluorescence intensity for increased intracellular free Ca 2+ levels in a reversible-and concentration-dependent manner in rat cortical neurons cultured for 3 to 15 days in vitro (DIV), while EC 50 values were significantly decreased in proportion to cellular maturation from 3 to 15 DIV. Although a constant increase was persistently seen in the fluorescence throughout the sustained exposure to NMDA for 60 min irrespective of the cell maturation from 3 to 15 DIV, the second brief exposure for 5 min resulted in a less efficient increase in the fluorescence than that found after the first brief exposure for 5 min in a manner dependent on intervals between the 2 repetitive brief exposures. In vitro maturation significantly shortened the interval required for the reduced responsiveness to the second brief exposure, while in immature neurons prolonged intervals were required for the reduced responsiveness to the second brief exposure to NMDA. Brief exposure to NMDA led to a marked decrease in immunoreactivity to extracellular loop of NR1 subunit after brief exposure to NMDA when determined in cultured neurons not permeabilized in proportion to the time after washing. These results suggest that cellular maturation would reduce the responsiveness to repeated stimulation by NMDA, without markedly affecting that to sustained exposure to NMDA, through the decrease in the number of membranous NMDA receptors in cultured rat cortical neurons.

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

Cited by 98 publications

References 46 publications

Retina-Driven Dephosphorylation of the NR2A Subunit Correlates with Faster NMDA Receptor Kinetics at Developing Retinocollicular Synapses

Retina-Driven Dephosphorylation of the NR2A Subunit Correlates with Faster NMDA Receptor Kinetics at Developing Retinocollicular Synapses

Lamotrigine blocks repeated high-dose methamphetamine-induced behavioral sensitization to dizocilpine (MK-801), but not methamphetamine in rats

Maturation-dependent reduced responsiveness of intracellular free Ca2+ ions to repeated stimulation by N-methyl-d-aspartate in cultured rat cortical neurons

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