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NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP,

Surojit Paul1, John A Connor

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

Journal of Neurochemistry
|June 8, 2010
PubMed

Insights

NMDA receptors control extracellular signal-regulated kinase (ERK) pathway activity through distinct calcium (Ca2+) signaling phases. NR2B-containing NMDA receptors mediate a delayed Ca2+ increase crucial for ERK inactivation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Signaling

Background:

  • NMDA receptors are critical for neuronal plasticity and survival.
  • ERK signaling cascade is a key pathway regulated by NMDA receptors.
  • The differential roles of NR2A- and NR2B-containing NMDA receptors in ERK regulation are not fully understood.

Purpose of the Study:

  • To elucidate the distinct roles of NR2A- and NR2B-containing NMDA receptors in regulating intracellular calcium (Ca2+) dynamics.
  • To understand the mechanisms by which these calcium changes influence extracellular signal-regulated kinase (ERK) pathway activation and inactivation.

Main Methods:

  • Utilized selective NMDA receptor inhibitors (Ifenprodil, Ro 25-6981) and a non-selective inhibitor (MK-801).
  • Measured glutamate-mediated intracellular Ca2+ increases in neurons.
  • Assessed the impact of Ca2+ signaling on ERK activation and striatal-enriched phosphatase activity.

Main Results:

  • Glutamate stimulation induced biphasic Ca2+ increases: a rapid initial phase and a delayed larger phase.
  • NR2B-selective inhibitors blocked the delayed Ca2+ increase but minimally affected the rapid phase.
  • The rapid Ca2+ increase activated ERK, while the delayed Ca2+ increase mediated by NR2B-NMDA receptors was essential for ERK inactivation via striatal-enriched phosphatase.

Conclusions:

  • The magnitude of Ca2+ influx through NR2B-NMDA receptors is a critical determinant of ERK activity.
  • Distinct NMDA receptor subunits differentially regulate Ca2+ signaling phases, leading to either ERK activation or inactivation.
  • This study reveals a novel mechanism for bidirectional control of ERK signaling by NMDA receptors, impacting neuronal function.

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