Kinetic characterization of the phencyclidine-N-methyl-D-aspartate receptor interaction: evidence for a steric blockade of the channel
The nature of the interactions between the N-methyl-D-aspartate (NMDA) and the phencyclidine (PCP) receptors was studied in membranes obtained from rat cerebral cortex and washed repeatedly to remove endogenous excitatory amino acids. Binding of (/sup 3/H)-N-(1-(2-thienyl)cyclohexyl)piperidine ((/sup 3/H)TCP) to its receptor sites in these membranes proceeded slowly and did not reach equilibrium even after incubation for 4 h at 25/sup 0/C. The dissociation rate of (/sup 3/H)TCP-receptor complexes was also slow. Both association and dissociation followed first-order reaction kinetics. Addition of glutamate and glycine to the washed membranes was immediately followed by a marked increase in the rates of both association of (/sup 3/H)TCP with the receptors and its dissociation from them. Association now followed second-order reaction kinetics. Accelerated association of (/sup 3/H)TCP with its binding sites could also be induced by NMDA or by glutamate alone, and glycine enhanced the effect. The binding data were fitted to a model in which interactions of (/sup 3/H)TCP with the receptor involve a two-step process: the outside ligand must cross a barrier (presumably a closed NMDA receptor channel in the absence of agonists). Once agonists are added, this limitation is removed. The excellent agreement between the kinetic and equilibrium binding parameters with the predictions of the model, as well as with previous electrophysiological data on the mode of noncompetitive blocking of the NMDA receptor channel by PCP-like drugs, suggests that these drugs are steric blockers of the channel and prefer its open state.
- Research Organization:
- Tel Aviv Univ. (Israel)
- OSTI ID:
- 5317239
- Journal Information:
- Biochemistry; (United States), Vol. 27:3
- Country of Publication:
- United States
- Language:
- English
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ANESTHETICS
CONFIGURATION INTERACTION
RECEPTORS
BIOCHEMICAL REACTION KINETICS
BRAIN
CELL MEMBRANES
GLUTAMIC ACID
GLYCINE
RATS
TRITIUM COMPOUNDS
AMINO ACIDS
ANIMALS
BODY
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DRUGS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
MEMBRANES
NERVOUS SYSTEM
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PROTEINS
REACTION KINETICS
RODENTS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques