Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes. Br J Pharmacol 2011 Aug;163(8):1755-66
Date
04/01/2011Pubmed ID
21449975Pubmed Central ID
PMC3166701DOI
10.1111/j.1476-5381.2011.01374.xScopus ID
2-s2.0-79960908335 (requires institutional sign-in at Scopus site) 97 CitationsAbstract
BACKGROUND AND PURPOSE: Astrocytes of the mouse neocortex express functional NMDA receptors, which are not blocked by Mg(2+) ions. However, the pharmacological profile of glial NMDA receptors and their subunit composition is far from complete.
EXPERIMENTAL APPROACH: We tested the sensitivity of NMDA receptor-mediated currents to the novel GluN2C/D subunit-selective antagonist UBP141 in mouse cortical astrocytes and neurons. We also examined the effect of memantine, an antagonist that has substantially different affinities for GluN2A/B and GluN2C/d-containing receptors in physiological concentrations of extracellular Mg(2+).
KEY RESULTS: UBP141 had a strong inhibitory action on NMDA receptor-mediated transmembrane currents in the cortical layer II/III astrocytes with an IC(50) of 2.29 µM and a modest inhibitory action on NMDA-responses in the pyramidal neurons with IC(50) of 19.8 µM. Astroglial and neuronal NMDA receptors exhibited different sensitivities to memantine with IC(50) values of 2.19 and 10.8 µM, respectively. Consistent with pharmacological differences between astroglial and neuronal NMDA receptors, NMDA receptors in astrocytes showed lower Ca(2+) permeability than neuronal receptors with P(Ca) /P(Na) ratio of 3.4.
CONCLUSIONS AND IMPLICATIONS: The biophysical and pharmacological properties of the astrocytic NMDA receptors strongly suggest that they have a tri-heteromeric structure composed of GluN1, GluN2C/D and GluN3 subunits. The substantial difference between astroglial and neuronal NMDA receptors in their sensitivity to UBP141 and memantine may enable selective modulation of astrocytic signalling that could be very helpful for elucidating the mechanisms of neuron-glia communications. Our results may also provide the basis for the development of novel therapeutic agents specifically targeting glial signalling.
Author List
Palygin O, Lalo U, Pankratov YMESH terms used to index this publication - Major topics in bold
Aniline CompoundsAnimals
Astrocytes
Calcium
Cerebral Cortex
Excitatory Amino Acid Agonists
Fluorescent Dyes
Green Fluorescent Proteins
Mice
Mice, Transgenic
N-Methylaspartate
Neurons
Patch-Clamp Techniques
Receptors, AMPA
Receptors, N-Methyl-D-Aspartate
Receptors, Purinergic P2X
Vesicular Glutamate Transport Proteins
Xanthenes
