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

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Palygin, Oleg, Lalo, Ulyana and Pankratov, Yuriy. (2011) Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes. British Journal of Pharmacology, Vol.163 (No.8). pp. 1755-1766. ISSN 1476-5381

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Official URL: http://dx.doi.org/10.1111/j.1476-5381.2011.01374.x

Abstract

Background and purpose Astrocytes of the mouse neocortex express functional NMDA receptors which are not blocked by Mg2+ions. However, study of the pharmacological profile of glial NMDARs and their subunit composition is far from complete. Experimental approach In the present study we tested the sensitivity of NMDA receptor-mediated currents in the cortical astrocytes and neurons to the novel GluN2C/D subunit-selective antagonist UBP141. We also examined the action of memantine, an antagonist reported to have substantially different affinities for GluN2A/B and GluN2C/D-containing receptors in physiological concentrations of extracellular Mg2+ . Key results UBP141 had a strong inhibitory action on NMDA receptor-mediated transmembrane currents in the cortical layer II/III astrocytes with an IC50 of 2.29 μM and a modest inhibitory action on NMDA-responses in the pyramidal neurons with IC50 of 19.8 μM. Astroglial and neuronal NMDA receptors exhibited different sensitivities to memantine with corresponding IC50 of 2.19 and 10.8 μM, respectively. Consistent with pharmacological differences between astroglial and neuronal NMDA receptors, NMDA receptors in astrocytes showed lower Ca2+-permeability than neuronal ones with PCa/PNa ratio of 3.4. Conclusions and Implications The combination of biophysical and pharmacological properties of astrocytic NMDA receptors strongly suggests they have tri-heteromeric structure composed of GluN1, GluN2C/D and GluN3 subunits. Dramatic 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 a clue for development novel therapeutic agents specifically targeting glial signalling.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Astrocytes, Neocortex, Neural transmission
Journal or Publication Title:	British Journal of Pharmacology
Publisher:	John Wiley & Sons Ltd.
ISSN:	1476-5381
Date:	August 2011
Volume:	Vol.163
Number:	No.8
Page Range:	pp. 1755-1766
Identification Number:	10.1111/j.1476-5381.2011.01374.x
Status:	Peer Reviewed
Access rights to Published version:	Restricted or Subscription Access
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC)
Grant number:	BB/F021445 (BBSRC)
References:	Agulhon C, Petravicz J, McMullen AB, Sweger EJ, Minton SK, Taves SR, Casper KB, Fiacco TA, McCarthy KD (2008). What is the role of astrocyte calcium in neurophysiology? Neuron 59:932-946. Bergles DE, Jabs R, Steinhauser C (2009). Neuron-glia synapses in the brain. Brain Res Rev 63:130-137. Brothwell SL, Barber JL, Monaghan DT, Jane DE, Gibb AJ, Jones S (2008). NR2B- and NR2D-containing synaptic NMDA receptors in developing rat substantia nigra pars compacta dopaminergic neurones. J Physiol 586:739-750. Burnashev N, Villarroel A Sakmann B (1996). Dimensions and ion selectivity of recombinant AMPA and kainate receptor channels and their dependence on Q/R site residues. J Physiol, London 496:165-173. Burzomato V, Frugier G, Perez-Otano I, Kittler JT, Attwell D (2010). The receptor subunits generating NMDA receptor mediated currents in oligodendrocytes. J Physiol 588:3403-3414. Cavara NA, Hollmann M (2008). Shuffling the deck anew: how NR3 tweaks NMDA receptor function. Mol Neurobiol 38:16-26. Cavara NA, Orth A, Hollmann M (2009). Effects of NR1 splicing on NR1/NR3B-type excitatory glycine receptors. BMC Neurosci 10:32. Castro NG, Albuquerque EX (1995). alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability. Biophys J 68:516-524. Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D (2002). Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415:793-798. Cull-Candy SG, Leszkiewicz DN (2004). Role of distinct NMDA receptor subtypes at central synapses. Sci STKE 2004:re16. Danbolt NC (2001). Glutamate uptake. Prog Neurobiol 65:1-105. Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, et al. (2010). Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 42:1021-1026. Erreger K, Geballe MT, Kristensen A, Chen PE, Hansen KB, Lee CJ, et al. (2007). Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors. Mol Pharmacol 72:907-920. Evans RJ, Lewis C, Virginio C, Lundstrom K, Buell G, Surprenant A, North RA (1996). Ionic permeability of, and divalent cation effects on, two ATP-gated cation channels (P2X receptors) expressed in mammalian cells. J Physiol 497 ( Pt 2):413-422. Fucile S (2004). Ca2+ permeability of nicotinic acetylcholine receptors. Cell Calcium 35:1-8. Furukawa H, Singh SK, Mancusso R, Gouaux E (2005). Subunit arrangement and function in NMDA receptors. Nature 438:185-192. Henson MA, Roberts AC, Perez-Otano I, Philpot BD (2010). Influence of the NR3A subunit on NMDA receptor functions. Prog Neurobiol 91:23-37. Hu WH, WaltersWM, Xia XM, Karmally SA, Bethea JR (2003). Neuronal glutamate transporter EAAT4 is expressed in astrocytes. Glia 44:13-25. Isa T, Itazawa S, Iino M, Tsuzuki K Ozawa S (1996). Distribution of neurones expressing inwardly rectifying and Ca2+-permeable AMPA receptors in rat hippocampal slices. J Physiol, London 491:719-733. Karadottir R, Cavelier P, Bergersen LH, Attwell D (2005). NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438:1162-1166. Kotermanski SE, Johnson JW (2009). Mg2+ Imparts NMDA Receptor Subtype Selectivity to the Alzheimer’s Drug Memantine. J Neurosci 29: 2774 –2779. Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A (2006). NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J Neurosci 26:2673-2683. Lalo U, Pankratov Y,Wichert SP, Rossner MJ, North RA, Kirchhoff F, Verkhratsky A (2008). P2X1 and P2X5 subunits form the functional P2X receptor in mouse cortical astrocytes. J Neurosci 28:5473-5480. Lewis C.A. (1979) Ion-concentration dependence of the reversal potential and single cell conductance of ion channel at the frog neuromuscular junction. Journal of Physiology (Lond) 286: 417-445 Iino M, Ozawa S, Tsuzuki K (1990). Permeation of calcium through excitatory amino acid receptor channels in cultured rat hippocampal neurones. J Physiol 424:151-165. Lipton SA (2006). NMDA receptors, glial cells, and clinical medicine. Neuron 50: 9-11. Matsuda K, Fletcher M, Kamiya Y, Yuzaki M (2003). Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors. J Neurosci 23:10064-10073. Matsui K, Jahr CE (2004). Differential control of synaptic and ectopic vesicular release of glutamate. J Neurosci 24:8932-8939. Matute C, Domercq M, Sanchez-GomezMV (2006). Glutamate-mediated glial injury: mechanisms and clinical importance. Glia 53:212-224. Mayer ML,Westbrook GL (1987). Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones. J Physiol 394:501-527. Micu I, Jiang Q, Coderre E, Ridsdale A, Zhang L, Woulfe J, Yin X, Trapp BD, McRory JE, Rehak R, Zamponi GW, Wang W, Stys PK (2006). NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439:988-992. Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994). Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12: 529-540. Morley RM, Tse HW, Feng B, Miller JC, Monaghan DT, Jane DE (2005). Synthesis and pharmacology of N1- substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists. JMed Chem 48:2627-2637. Nolte C, Matyash M, Pivneva T, Schipke CG, Ohlemeyer C, Hanisch UK, Kirchhoff F, Kettenmann H (2001). GFAP promoter-controlled EGFP-expressing transgenic mice: a tool to visualize astrocytes and astrogliosis in living brain tissue. Glia 33:72-86. Pankratov Y, Lalo U, Krishtal O, Verkhratsky A (2002). Ionotropic P2X purinoreceptors mediate synaptic transmission in rat pyramidal neurones of layer II/III of somato-sensory cortex. J Physiol 542:529-536. Paoletti P, Neyton J (2007). NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol 7:39-47. Qian A, Johnson JW(2006). Permeant ion effects on external Mg2+ block of NR1/2D NMDA receptors. J Neurosci 26:10899-10910. Sasaki YF, Rothe T, Premkumar LS, Das S, Cui J, Talantova MV,Wong HK, Gong X, Chan SF, Zhang D, Nakanishi N, Sucher NJ, Lipton SA (2002). Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons. J Neurophysiol 87:2052-2063. Smothers CT,Woodward JJ (2009). Expression of glycine-activated diheteromeric NR1/NR3 receptors in human embryonic kidney 293 cells Is NR1 splice variant-dependent. J Pharmacol Exp Ther 331:975-984. Steinert JR, Postlethwaite M, JordanMD, Chernova T, Robinson SW, Forsythe (2010). NMDAR-mediated EPSCs are maintained and accelerate in time course during maturation of mouse and rat auditory brainstem in vitro. J Physiol 588:447-463. Tong G, Takahashi H, Tu S, Shin Y, Talantova M, ZagoW, Xia P, Nie Z, Goetz T, Zhang D, Lipton SA, Nakanishi N (2008). Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons. J Neurophysiol 99:122-132. Wrighton DC, Baker EJ, Chen PE,Wyllie DJ (2008). Mg2+ and memantine block of rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes. J Physiol 586:211-225.
URI:	http://wrap.warwick.ac.uk/id/eprint/36776