Determinants of Phencyclidine Potency on the Nicotinic Acetylcholine Receptors from Muscle and Electric Organ |
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Authors: | Vesna A Eterović Ruiliang Lu Ann E Eakin Abimael D Rodríguez P A Ferchmin |
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Institution: | (1) Department of Biochemistry, Universidad Central del Caribe, Bayamon, Puerto Rico, 00960;(2) Center for Molecular and Behavioral Neuroscience, Universidad Central del Caribe, Bayamon, Puerto Rico, 00960;(3) Present address: Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore, Baltimore, Maryland, 21202;(4) Department of Biochemistry and Nutrition, University of Puerto Rico School of Medicine, Medical Sciences Campus, Rio Piedras, Puerto Rico, 00936;(5) Present address: Present address: Division of Medicinal Chemistry and Natural Products, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7360;(6) Present address: Department of Chemistry, University of Puerto Rico at Rio Piedras, Rio Piedras, Puerto Rico, 00931 |
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Abstract: | 1.Phencyclidine (PCP) is an inhibitor of the nicotinic acetylcholine receptor (AChR) with characteristics of an open-channel blocker. The location of PCP binding site on the AChR molecule is unknown.2.PCP inhibits the AChR from electric organ with a higher potency than muscle AChR. To find the molecular basis of this difference, we expressed the two native and six hybrid receptors, and two receptors containing mutated mouse subunits in Xenopus laevis oocytes. The inhibition of ACh-induced current in these receptors by PCP was studied using whole-cell voltage-clamp. All hybrid receptors generated robust ACh-induced currents, while incomplete receptors ( -less or -less) did not.3.PCP potency was higher on hybrids containing Torpedo and subunits regardless of the and subunit origin. A mouse subunit containing the asparagine 6 to the serine mutation in the M2 segment conferred a high sensitivity to PCP.4.These results support the conclusion that the amino acid residues at the position 6 of the M2 segments contribute to the PCP potency difference between Torpedo and mouse receptors.5.Another noncompetitive inhibitor of the AChR, the cembranoid eupalmerin acetate (EUAC), also inhibited the electric organ receptor with a somewhat higher potency than muscle AChR. However, the IC50 values for EUAC inhibition of hybrid receptors did not follow the pattern observed for PCP. Therefore, these two inhibitors interact differently with the AChR molecule. |
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Keywords: | nicotinic acetylcholine receptor phencyclidine electric organ Xenopus oocytes voltage clamp eupalmerin acetate Cembranoids |
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