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J Neurochem. 2010 Aug;114(4):1107-18. doi: 10.1111/j.1471-4159.2010.06835.x. Epub 2010 May 28.

NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP, and ERK MAP kinase signaling.

Author information

1
Department of Neurology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico 87131, USA. spaul@salud.unm.edu

Abstract

NMDA receptors regulate both the activation and inactivation of the extracellular signal-regulated kinase (ERK) signaling cascade, a key pathway involved in neuronal plasticity and survival. This bi-directional regulation of ERK activity by NMDA receptors has been attributed to opposing actions of NR2A- versus NR2B-containing NMDA receptors, but how this is implemented is not understood. Here, we show that glutamate-mediated intracellular Ca(2+) increases occur in two phases, a rapid initial increase followed by a delayed larger increase. Both phases of the Ca(2+) increase were blocked by MK-801, a non-selective NMDA receptor inhibitor. On the other hand, selective inhibition of NR2B-NMDA receptors by Ifenprodil or Ro 25-6981 blocked the delayed larger phase but had only a small effect on the rapid initial increase. The rapid initial increase in Ca(2+), presumably because of NR2A-NMDAR activation, was sufficient to activate ERK, whereas the large delayed increases in Ca(2+) mediated by NR2B-NMDARs were necessary for dephosphorylation and subsequent activation of striatal-enriched phosphatase, a neuron-specific tyrosine phosphatase that in turn mediates the dephosphorylation and inactivation of ERK. We conclude that the magnitude of Ca(2+) increases mediated through NR2B-NMDA receptors plays a critical role in the regulation of the serine/threonine and tyrosine kinases and phosphatases that are involved in the regulation of ERK activity.

PMID:
20524968
PMCID:
PMC3049732
DOI:
10.1111/j.1471-4159.2010.06835.x
[Indexed for MEDLINE]
Free PMC Article

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