Molecular Pharmacology, Vol 18, 167-178, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Sites of Action of Phencyclidine

II. Interaction with the Ionic Channel of the Nicotinic Receptor

¹ Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201

The effects of phencyclidine (PCP) were studied on the endplate current (EPC), miniature endplate current (MEPC), and synaptic noise of the frog sartorius muscle and on the binding of [³H]perhydrohistrionicotoxin ([³H]H₁₂-HTX) to the ionic channel of the acetylcholine (ACh) receptor in electric organ membranes of Torpedo ocellata. PCP decreased the peak amplitude of the EPC in a voltage- and time-dependent manner, caused nonlinearity in the current-voltage relationship, accelerated the decay time constants of the EPC and MEPC, and shortened the mean lifetime of the single ionic channel. PCP also inhibited binding of [³H]H₁₂-HTX to the ionic channel of the ACh receptor with a K_i, of 6.9 µM. When carbamyicholine was present to activate the ACh receptors, the K_d value for PCP binding to ionic channel sites was reduced from 10.3 ± 4.2 to 2.0 ± 1.3 µM, thus showing higher affinity for the activated ionic channel sites. In addition, PCP also reacted with the closed ionic channel since a time-dependent effect on EPC amplitude in hyperpolarized membranes was observed even before the ACh receptor was activated. Further, PCP depressed peak EPC amplitude more markedly than it shortened the EPC decay time constant, thus disclosing that the depression of the former cannot be accounted for totally by the action of the agent on the open conformation of the ionic channel. A hybrid model was proposed to account for the interactions of PCP with the open and closed states of the ionic channel of the ACh receptor. The actions of PCP on both states of the ionic channel are qualitatively similar to those seen with histrionicotoxin.

Note:
ACKNOWLEDGMENTS We are grateful to Dr. John Daly of the National Institutes of Health for kindly providing us with labeled and unlabeled perhydrohistrionicotoxin and to Ms. Mabel Alice Zelle for the computer analyses.

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