NMDA-induced ERK signalling is mediated by NR2B subunit in rat cortical neurons and switches from positive to negative depending on stage of development

• Published in: Neuropharmacology Vol. 62; no. 2; pp. 925 - 932
• Main Authors: Sava, Anna, Formaggio, Elena, Carignani, Corrado, Andreetta, Filippo, Bettini, Ezio, Griffante, Cristiana
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-02-2012
• Subjects: Animals; Antagonists; Calcium (intracellular); Cell survival; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cortex; Developmental stages; Extracellular signal-regulated kinase; Extracellular signal-regulated kinase (ERK); Extracellular Signal-Regulated MAP Kinases - metabolism; FLIPR; Glutamic acid receptors (ionotropic); MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; N-Methyl-D-aspartic acid receptors; N-Methylaspartate - pharmacology; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; NMDA receptor antagonist; NR2B receptor; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - physiology; Plasticity (neural); Rat cortical neurons; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - metabolism; Signal transduction; Stress; probenecid; NR2B receptor; ifenprodil; memantine; NMDA receptor antagonist; (+)-MK-801; HEK; Extracellular signal-regulated kinase (ERK); Ro 25-6981; PSS; Rat cortical neurons; CP-101,606; NMDA; FLIPR; HBSSH; NVP-AAM077; U0126; ERK
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2011.09.025

It is known that NMDA receptor stimulation can activate or inhibit the extracellular signal-regulated kinase (ERK) signalling cascade, a key pathway involved in neuronal plasticity and survival. However, the specific subtype(s) of NMDA receptor that exert bi-directional regulation of ERK signalling is under debate. Here we show that in young neurons (7–9 days in vitro, DIV), NMDA activated ERK signalling. In mature neurons (14–16 DIV), NMDA-evoked, in coincidence with a concentration-dependent increase in intracellular Ca
2+ ([Ca
2+]
i), an increase in ERK phosphorylation at low concentrations (1–30 μM) while an inhibition at high concentrations (30 μM-250 μM). In more mature neurons (21–23 DIV) NMDA inhibited ERK signalling. Both activation and inhibition of ERK signalling were fully reversed by the selective NR2B receptor antagonists Ro 25-6981 and ifenprodil. Thus, the NR2B subunit can be both negatively or positively coupled to ERK signalling in rat cortical neurons, depending on their stage of development.
This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.
► NR2B subunit regulates ERK signalling in cultured neurons. ► NR2B subunit activates or inhibits ERK depending on neuronal stage of development. ► NR2B ligands Ro 25-6981 and CP-101,606 show an age-dependent different pharmacology.