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First published on June 13, 2005; DOI: 10.1124/mol.105.014431

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Received for publication May 3, 2005.
Revised June 3, 2005.
Accepted for publication June 13, 2005.

Effects of Quinine, Quinidine and Chloroquine on {alpha}9{alpha}10 Nicotinic Cholinergic Receptors

Jimena A Ballestero 1, Paola V Plazas 1, Sebastian Kracun 2, Maria E. Gomez-Casati 1, Julian Taranda 1, Carla V Rothlin 1, Eleonora Katz 3, Neil S Millar 2, A. Belen Elgoyhen 1*

1 Instituto de Investigaciones en Ingenieria Genetica y Biologia Molecular (CONICET-UBA) 2 Department of Pharmacology, University College London 3 IInstituto de Investigaciones en Ingenieria Genetica y Biologia Molecular (CONICET-UBA)

* Address correspondence to: E-mail: elgoyhen{at}dna.uba.ar

Abstract

In the present study, we report the effects of the quinoline derivatives, quinine, its optical isomer quinidine and chloroquine on {alpha}9{alpha}10-containing nicotinic cholinergic receptors (nAChRs). The compounds blocked acetylcholine (ACh)-evoked responses in {alpha}9{alpha}10-injected Xenopus laevis oocytes in a concentration-dependent manner, with a rank order of potency of: chloroquine (IC50: 0.39 µM) > quinine (IC50: 0.97 µM) ~ quinidine (IC50: 1.37 µM). Moreover, chloroquine blocked ACh-evoked responses on rat cochlear inner hair cells with an IC50 value, 0.13 µM, within the same range as that observed for recombinant receptors. Block by chloroquine was purely competitive, whereas quinine inhibited ACh currents in a mixed competitive and noncompetitive manner. The competitive nature of the blockage produced by the three compounds was confirmed by equilibrium binding experiments using [3H]-methyllycaconitine (MLA). Binding affinities (Ki values) were: 2.3, 5.5 and 13.0 µM for chloroquine, quinine and quinidine, respectively. Block by quinine was found to be only slightly voltage dependent, thus precluding open channel block as the main mechanism of interaction of quinine with {alpha}9{alpha}10 nAChRs. The present results add to the pharmacological characterization of {alpha}9{alpha}10-containing nicotinic receptors and indicate that the efferent olivocochlear system that innervates the cochlear hair cells is a target of these ototoxic antimalarial compounds.


Key words: Nicotinic cholinergic, Receptor binding studies




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