Adenosine triphosphate acts as both a competitive antagonist and a positive allosteric modulator at recombinant N-methyl-D-aspartate receptors

Kloda, A., Clements, J. D., Lewis, R. J. and Adams, D. J. (2004) Adenosine triphosphate acts as both a competitive antagonist and a positive allosteric modulator at recombinant N-methyl-D-aspartate receptors. Molecular Pharmacology, 65 6: 1386-1396. doi:10.1124/mol.65.6.1386


Author Kloda, A.
Clements, J. D.
Lewis, R. J.
Adams, D. J.
Title Adenosine triphosphate acts as both a competitive antagonist and a positive allosteric modulator at recombinant N-methyl-D-aspartate receptors
Journal name Molecular Pharmacology   Check publisher's open access policy
ISSN 0026-895X
Publication date 2004-06-01
Year available 2004
Sub-type Article (original research)
DOI 10.1124/mol.65.6.1386
Open Access Status DOI
Volume 65
Issue 6
Start page 1386
End page 1396
Total pages 11
Place of publication Bethesda, USA
Publisher American Society of Pharmacology Experimental Therapeutics
Language eng
Subject C1
320305 Medical Biochemistry - Proteins and Peptides
730104 Nervous system and disorders
Abstract ATP and glutamate are fast excitatory neurotransmitters in the central nervous system acting primarily on ionotropic P2X and glutamate [N-methyl-D-aspartate (NMDA) and non-NMDA] receptors, respectively. Both neurotransmitters regulate synaptic plasticity and long-term potentiation in hippocampal neurons. NMDA receptors are responsible primarily for the modulatory action of glutamate, but the mechanism underlying the modulatory effect of ATP remains uncertain. In the present study, the effect of ATP on recombinant NR1a + 2A, NR1a + 2B, and NR1a + 2C NMDA receptors expressed in Xenopus laevis oocytes was investigated. ATP inhibited NR1a + 2A and NR1a + 2B receptor currents evoked by low concentrations of glutamate but potentiated currents evoked by saturating glutamate concentrations. In contrast, ATP potentiated NR1a + 2C receptor currents evoked by nonsaturating glutamate concentrations. ATP shifted the glutamate concentration-response curve to the right, indicating a competitive interaction at the agonist binding site. ATP inhibition and potentiation of glutamate-evoked currents was voltage-independent, indicating that ATP acts outside the membrane electric field. Other nucleotides, including ADP, GTP, CTP, and UTP, inhibited glutamate-evoked currents with different potencies, revealing that the inhibition is dependent on both the phosphate chain and nucleotide ring structure. At high concentrations, glutamate outcompetes ATP at the agonist binding site, revealing a potentiation of the current. This effect must be caused by ATP binding at a separate site, where it acts as a positive allosteric modulator of channel gating. A simple model of the NMDA receptor, with ATP acting both as a competitive antagonist at the glutamate binding site and as a positive allosteric modulator at a separate site, reproduced the main features of the data.
Keyword Pharmacology & Pharmacy
Long-term Potentiation
Nmda Receptors
Synaptic Transmission
Rat Hippocampus
Binding-sites
P2x Receptors
Guanine-nucleotides
Nervous-system
Acid Receptors
Atp
Q-Index Code C1
Institutional Status UQ

 
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Created: Wed, 15 Aug 2007, 15:20:52 EST