Phencyclidine in nanomolar concentrations binds to synaptosomes and blocks certain potassium channels.

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Abstract
Phencyclidine (PCP, [a drug of abuse]), in low dose (.apprxeq. 0.1-0.2 mg/kg of body wt), induces a schizophrenia-like behavioral syndrome in man; this effect has been attributed to block of neuronal K channels. A K-stimulated 86Rb efflux assay was used 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 (> 10 .mu.M) 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 .apprxeq. 6.0 .times. 10-8 M), and to other components with much lower affinity (Kd .apprxeq. 1.15 .times. 104 M). PCP can be photoactivated with UV light to form covalent bonds: after UV irradiation, previously-bound [3H]PCP is not longer displaceable by a large excess of unlabeled PCP. Preliminary data from NaDodSO4[sodium dodecylsulfate]/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 (MW .apprxeq. 220,000). The high-affinity PCP binding protein may be 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 Ca entry and neurotransmitter release, thereby altering transmission at central synapses involved in behavioral expression.