Mercury (Hg 2+ ) suppression of potassium currents of outer hair cells G.-H. Liang a , L. Ja ¨rlebark a , M. Ulfendahl a , E.J. Moore b, * a ENT Research Laboratory and Institute for Hearing and Communication Research, Karolinska Institutet, SE-171 76 Stockholm, Sweden b Northwestern Drug Discovery Program, Department of Molecular Pharmacology and Biological Chemistry (S215), The Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA Received 6 August 2002; received in revised form 31 December 2002; accepted 2 January 2003 Abstract The heavy metal mercury (Hg 2+ ) is an insidious environmental pollutant that causes toxic effects on sensory systems. It is well known that the group IIB divalent cation Hg 2+ is an inhibitor of the group I monovalent potassium (K + ) cation pore-forming channel in several biological preparations. Here, we used the whole cell patch clamp technique on freshly isolated outer hair cells (OHCs) of the guinea pig cochlea to record outward K + currents and inward K + currents treated with mercuric chloride (HgCl 2 ). HgCl 2 affected K + currents in a voltage- and dose-dependent manner. The effects of HgCl 2 at 1.0 – 100 mM are more pronounced on onset peak current than on steady-state end current. HgCl 2 depolarized also the resting membrane potential. Although the effect of HgCl 2 at 1.0 mM was partially washed out over several minutes, the effects at 10 and 100 mM were irreversible to washout. Since K + channels of OHCs are targets for HgCl 2 ototoxicity, this may lead to auditory transduction problems, including a loss in hearing sensitivity. A better understanding of fundamental mechanisms underlying K + channelopathies in OHCs due to HgCl 2 poisoning may lead to better preventive or therapeutic agents. D 2003 Elsevier Science Inc. All rights reserved. Keywords: Cochlea; Potassium channels; Outer hair cells; Mercuric chloride (HgCl 2 ); K + outward currents; K + inward currents 1. Introduction Neurotoxicity of organic (MeHg) or inorganic (Hg 2+ ) mercury has been well documented in both humans [8,13,14,19,29,32,33,35,48] and experimental animals [1,11,28,29,31,40,47]. The developing premature and immature CNS is more sensitive to damage from MeHg than the adult CNS [8,13]. In general, weeks or months are needed to manifest phenotypic conditions due to Hg 2+ such as hearing loss, ataxia, weakness and visual and sensory changes from acute or chronic Hg 2+ poisoning [17,32,33]. The auditory deficit extends almost over the entire fre- quency range of hearing, and in the most severe instances, Hg 2+ can lead to clinically significant auditory deficits [4,19,35]. The sensory cochlea and vestibular apparatus of the inner ear containing the hair cells and central auditory structures have been a target of Hg 2+ ototoxicity [4,9,14, 16,17,24,26,35,40,43,47]. In various biological preparations, Hg 2+ has been shown to increase intracellular free Ca 2+ [20,42]. Nerve and muscle membranes are also affected by mercuric chloride (HgCl 2 ) and MeHg [3,6,7,12,25,34,39], and volt- age-activated calcium [10,28,29,37,41,46], sodium [38], chloride [12,23] and potassium (K + ) [11,15,18,38] chan- nels are similarly suppressed. The GABA receptor channel [5,22,36], the Na, K-ATPase pump and excitatory amino acid receptors [31] have also been the target of Hg 2+ modulation. While the effects of Hg 2+ on several biological prepa- rations have been studied [3,32,33], the effects of Hg 2+ on patch clamp electrophysiology of outer hair cells (OHCs), however, have not been the subject of attention. Thus, the basis for possible differential modulation by different con- centrations of Hg 2+ on OHCs is unknown. There are several well-known K + conductances in OHC of guinea pig and they are believed to play an important role in frequency tuning, subthreshold excitability and maintaining the resting membrane potential [30]. The effects of Hg 2+ on K + channels were of primary interest since the stereocilia of OHCs are bathed in endolymph, which has a high concen- tration of K + ions, and pores conducting K + conductances 0892-0362/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0892-0362(03)00008-4 * Corresponding author. Tel.: +1-312-503-1736, +1-312-503-2658; fax: +1-312-503-1700. E-mail address: mooreer@northwestern.edu (E.J. Moore). www.elsevier.com/locate/neutera Neurotoxicology and Teratology 25 (2003) 349 – 359