Effects of membrane fluidity on [3H]TCP binding to PCP receptors.
Phencyclidine (PCP) binds with high affinity to the ion channel associated with the NMDA receptor. The binding of the PCP receptor-specific ligand TCP is greatly reduced at temperatures between 2 degrees C and 6 degrees C, at which the plasma membrane is in a rigid state. However, membrane rigidity alone does not appear to cause the reduced TCP binding, since the membrane fluidizing agent A2C did not increase TCP binding at 4 degrees C; instead, it decreased binding at 21 degrees C. This inhibitory effect of A2C on TCP binding was dose dependent and was highly correlated with A2C-induced increases in membrane fluidity. The IC50 of A2C inhibition was 8.9 mM, with a pseudo-Hill coefficient of -0.24. Scatchard analysis demonstrated that this effect was the result of an increase in the apparent KD of [3H]TCP for the PCP receptor, with no effect on the Bmax. These results suggest that the function of the NMDA-PCP receptor complex is impaired by increases in membrane fluidity. These findings may be pharmacologically relevant in understanding the mechanism of action of such agents as general anesthetics and ethanol, which cause increases in plasma membrane fluidity.
DePietro
F R
FR
Department of Psychiatry, University of Pittsburgh, Pennsylvania.
Byrd
J C
JC
D000818:Animals; D008560:Membrane Fluidity / Q000187:drug effects; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D017478:Receptors, Phencyclidine; D013228:Stearates / Q000494:pharmacology; D013696:Temperature; D014316:Tritium
D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D013228:Stearates; D014316:Tritium; C023714:A(2)C; C012058:tenocyclidine; D010622:Phencyclidine