Brain Research 882 (2000) 155–168 www.elsevier.com / locate / bres Research report Choline and acetylcholine have similar kinetic properties of activation and desensitization on the a7 nicotinic receptors in rat hippocampal neurons a ,1 b a,b, * Arpad Mike , Newton G. Castro , Edson X. Albuquerque a Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W . Baltimore St., Baltimore, MD 21201, USA b ´ ´ Departamento de Farmacologia Basica e Clınica, ICB, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-590, Brazil Accepted 15 August 2000 Abstract The a7-type nicotinic acetylcholine receptor (nAChR) was recently found to be both fully activated and desensitized by choline, in addition to ACh. In order to understand the combined effects of the two agonists on a7 nAChR-mediated neuronal signaling, the kinetics of the receptor-channel’s interaction with ACh and choline was examined. To this end, whole-cell and single-channel currents evoked by fast-switching pulses of the agonists were recorded in rat hippocampal neurons in culture. Currents evoked by equieffective concentrations of choline and ACh were very similar, except that choline-evoked currents decayed more quickly to the baseline after removal of the agonist, and that recovery from desensitization was faster with choline. The conductance of channels activated by choline and ACh was 91.568.5 and 82.9611.6 pS, respectively. The mean apparent channel open times were close to 100 ms, with both agonists. After a 4-s exposure to concentrations up to 80 mM ACh or 600 mM choline, the extent of desensitization and the cumulative charge flow carried by the channels increased in the same proportion, until reaching a maximum. At higher concentrations of either agonist, the cumulative charge started decreasing with concentration, reflecting further desensitization. Kinetic modeling suggested that a7 nAChRs have at least two non-equivalent paths to desensitized states, and that choline dissociates faster than ACh from the receptor. Our results established that the main difference between choline and ACh is of affinity, and support the concept that the switching of endogenous agonist may change the desensitization–resensitization dynamics of a7 nAChRs.  2000 Elsevier Science B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: Acetylcholine receptors: nicotinic Keywords: Choline; Alpha7; Nicotinic receptors; Hippocampus; Patch clamp; Kinetics 1. Introduction function in the central nervous system, particularly in the hippocampus [2–4,6,10,18,19,23,37]. These receptors are A large body of evidence has been accumulated indicat- located both postsynaptically in fresh hippocampal tissue ing that there is a direct participation of nicotinic acetyl- [4,18,22] and presynaptically, where they act by modu- choline receptors (nAChRs) in the control of neuronal lating transmitter release [1,5,7,19,20,23]. While more than one nAChR subtype is expressed in the hippocampus, sometimes with co-expression in single neurons [3,12,37], *Corresponding author. Department of Pharmacology and Experimen- tal Therapeutics, University of Maryland School of Medicine, 655 W. the a7-type nAChRs are by far the most abundant in Baltimore St., Baltimore, MD 21201, USA. Tel.: 11-410-706-7333; fax: cultured neurons [3,4,18] 11-410-706-3991. An important advance in understanding the function of E-mail address: ealbuque@umaryland.edu (E.X. Albuquerque). 1 nAChRs in the CNS was the demonstration that choline, a Present address: Department of Pharmacology, Institute of Experimen- precursor and metabolite of ACh, is an effective agonist of tal Medicine, Hungarian Academy of Sciences, P.O. Box 67, H-1450 Budapest, Hungary. a7 nAChRs [6,26,29]. It was recently demonstrated that 0006-8993 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0006-8993(00)02863-8