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

Authors: Paul, Surojit; Connor, John A.

Source: Journal of Neurochemistry, Volume 114, Number 4, August 2010 , pp. 1107-1118(12)

Publisher: Wiley-Blackwell

Abstract:

J. Neurochem. (2010) 114, 1107-1118. 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 Ca²⁺ increases occur in two phases, a rapid initial increase followed by a delayed larger increase. Both phases of the Ca²⁺ 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 Ca²⁺, presumably because of NR2A-NMDAR activation, was sufficient to activate ERK, whereas the large delayed increases in Ca²⁺ 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 Ca²⁺ 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.

Keywords: calcium; extracellular-regulated kinase; NMDA; striatal-enriched phosphatase; tyrosine phosphatase

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1471-4159.2010.06835.x

Affiliations: 1: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico

Publication date: 2010-08-01

Related content

• In this: publication
• By this: publisher
• In this Subject: Anatomy & Physiology
• By this author: Paul, Surojit ;  Connor, John A.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers