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Volume 16, Number 24, Issue of December 15, 1996 pp. 7880-7891
Copyright ©1996 Society for Neuroscience

Human 42 Neuronal Nicotinic Acetylcholine Receptor in HEK 293 Cells: A Patch-Clamp Study

Received Aug. 2, 1996; revised Sept. 16, 1996; accepted Sept. 30, 1996.

Bruno Buisson¹, Murali Gopalakrishnan², Stephen P. Arneric², James P. Sullivan², and Daniel Bertrand¹

¹ Department of Physiology, Faculty of Medicine, University of Geneva, CH-1211 Geneva 4, Switzerland, and ² Neuroscience Research, Abbott Laboratories, Abbott Park, Illinois 60064-3500

The cloning and expression of genes encoding for the human neuronal nicotinic acetylcholine receptors (nAChRs) has opened new possibilities for investigating their physiological and pharmacological properties. Cells (HEK 293) stably transfected with two of the major brain subunits, 4 and 2, were characterized electrophysiologically using the patch-clamp technique. Fast application of the natural ligand ACh can evoke currents up to 3500 pA, with an apparent affinity (EC₅₀) of 3 µM and a Hill coefficient of 1.2. The rank order of potency of four nAChR ligands to activate human 42 receptors is ()-nicotine > ACh > ()-cytisine > ABT-418. At saturating concentrations, the efficacy of these ligands is ABT-418  ()-nicotine > ACh  ()-cytisine > GTS-21 (previously named DMXB). Coapplication of 1 µM ACh with known nAChR inhibitors such as dihydro--erythroidine and methyllycaconitine reversibly reduces the current evoked by the agonist with respective IC₅₀ values of 80 nM and 1.5 µM. The current-voltage relationship of human 42 displays a strong rectification at positive potentials. Experiments of ionic substitutions suggest that human 42 nAChRs are permeable to sodium and potassium ions. In the ``outside-out'' configuration, ACh evokes unitary currents (main conductance 46 pS) characterized by a very fast rundown. Potentiation of the ACh-evoked currents is observed when the extracellular calcium concentration is increased from 0.2 to 2 mM. In contrast, however, a reduction of the evoked currents is observed when calcium concentration is elevated above 2 mM.

Key words: human; 42; neuronal; nicotinic; acetylcholine; receptor

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