Phencyclidine in nanomolar concentrations binds to synaptosomes and blocks certain potassium channels.
Phencyclidine [1-(phenylcyclohexyl)piperidine; PCP], in low dose (approximately equal to 0.1-0.2 mg/kg of body weight), induces a schizophrenia-like behavioral syndrome in man; this effect has been attributed to block of neuronal K channels. We used a K-stimulated 86Rb efflux assay to demonstrate that low concentrations of PCP (10-50 nM) block a class of depolarization-activated K channels in rat brain synaptosomes--pinched-off presynaptic nerve terminals. The dose-response curve is biphasic, and much higher PCP concentrations (greater than 10 microM) are required to block the remainder of the K-stimulated 86Rb efflux. The [3H]PCP binding curve for synaptosomes is also biphasic: PCP binds to some components with high affinity (Kd approximately equal to 6.0 X 10(-8) M), and to other components with much lower affinity (Kd approximately equal to 1.15 X 10(4) M). PCP can be photoactivated with UV light to form covalent bonds: after UV irradiation, previously-bound [3H]PCP is no longer displaceable by a large excess of unlabeled PCP. Preliminary data from NaDodSO4/polyacrylamide gel electrophoresis studies after covalent binding of [3H]PCP to synaptosomes, suggest that the high-affinity binding site may be on a large protein (Mr approximately equal to 220,000). We conclude that the high-affinity PCP binding protein is associated with the K channels that are blocked by nanomolar concentrations of PCP. Block of these channels could, by prolonging action-potential duration in presynaptic nerve terminals, enhance calcium entry and neurotransmitter release, thereby altering transmission at central synapses involved in behavioral expression.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D010622:Phencyclidine / Q000378:metabolism* / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D017478:Receptors, Phencyclidine; D012413:Rubidium / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D007473:Ion Channels; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D010622:Phencyclidine; D012413:Rubidium; D011188:Potassium