Kinetics Of Desensitization And Recovery From Desensitization For Human α4Β2-Nicotinic Acetylcholine Receptors Stably Expressed In Sh-Ep1 Cells



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Aim: Studies were conducted to define the kinetics of the onset of and recovery from desensitization for human α4Β2-nicotinic acetylcholine receptors (nAChR) heterologously expressed in the SH-EP1 human epithelial cell line. Methods: Whole-cell patch clamp recordings were performed to evaluate α4Β2-nAChR currents. Results: Application of 0.1 mol/L nicotine or 1 mmol/L acetylcholine (ACh) for 1 s or longer induced two phases, with time constants of 70 and 700 ms, for the onset of α4Β2-nAChR desensitization. For a given duration of agonist exposure, recovery from desensitization induced by nicotine was slower than recovery from ACh-induced desensitization. Comparisons with published reports indicate that time constants for the recovery of α4Β2-nAChRs from desensitization are smaller than those for the recovery of human muscle-type nAChRs 1 from desensitization produced by the same concentrations and durations of exposure to an agonist. Moreover, the extent of human α4Β2-nAChR desensitization and rate of recovery are the same, regardless of whether they are measured using whole-cell recording or based on published findings 2 using isotopic ion flux assays; this equality demonstrates the equivalent legitimacy of these techniques in the evaluation of nAChR desensitization. Perhaps most significantly, recovery from desensitization also was best fit to a biphasic process. Regardless of whether it was fit to single or double exponentials, however, half-times for recovery from desensitization grew progressively longer with an increased duration of agonist exposure during the desensitizing pulse. Conclusion: These findings indicate the existence of α4Β2-nAChRs in many distinctive states of desensitization, as well as the induction of progressively deeper states of desensitization with the increased duration of agonist exposure. © 2009 CPS and SIMM.

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Acta Pharmacologica Sinica







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