Dataset Information

Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes.

ABSTRACT:

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.

SUBMITTER: Palygin O

PROVIDER: S-EPMC3166701 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Publications

Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes.

Palygin Oleg O Lalo Ulyana U Pankratov Yuriy Y

British journal of pharmacology 20110801 8

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>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 tha ...[more]

PMID: 21449975

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Project description:Key pointsTriheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the CNS. Triheteromeric GluN1/2B/2D receptors have functional properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. GluN1/2B/2D receptors are more sensitive to channel blockade by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg2+ . GluN2B-selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B-selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. These insights into the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors.AbstractTriheteromeric NMDA-type glutamate receptors that contain two GluN1 and two different GluN2 subunits contribute to excitatory neurotransmission in the adult CNS. In the present study, we report properties of the triheteromeric GluN1/2B/2D NMDA receptor subtype that is expressed in distinct neuronal populations throughout the CNS. We show that neither GluN2B, nor GluN2D dominate the functional properties of GluN1/2B/2D receptors because agonist potencies, open probability and the glutamate deactivation time course of GluN1/2B/2D receptors are intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. Furthermore, channel blockade of GluN1/2B/2D by extracellular Mg2+ is intermediate compared to GluN1/2B and GluN1/2D, although GluN1/2B/2D is more sensitive to blockade by ketamine and memantine compared to GluN1/2B in the presence of physiological Mg2+ . Subunit-selective allosteric modulators have distinct activity at GluN1/2B/2D receptors, including GluN2B-selective antagonists, ifenprodil, EVT-101 and CP-101-606, which inhibit with similar potencies but with different efficacies at GluN1/2B/2D (∼65% inhibition) compared to GluN1/2B (∼95% inhibition). Furthermore, the GluN2B-selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. We show that these key features of allosteric modulation of recombinant GluN1/2B/2D receptors are also observed for NMDA receptors in hippocampal interneurons but not CA1 pyramidal cells, which is consistent with the expression of GluN1/2B/2D receptors in interneurons and GluN1/2A/2B receptors in pyramidal cells. Altogether, we uncover previously unknown functional and pharmacological properties of triheteromeric GluN1/2B/2D receptors that can facilitate advances in our understanding of their physiological roles in neural circuit function and therapeutic drug actions.

Dataset Information

Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes.

Similar Datasets

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