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J. Biol. Chem., Vol. 279, Issue 53, 55060-55072, December 31, 2004

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The TRK1 Potassium Transporter Is the Critical Effector for Killing of Candida albicans by the Cationic Protein, Histatin 5^*

Didi Baev, Alberto Rivetta, Slavena Vylkova, Jianing N. Sun, Ge-Fei Zeng, Clifford L. Slayman, and Mira Edgerton¶||

From the Departments of Oral Biology and ^¶Restorative Dentistry, School of Dental Medicine, State University of New York, Buffalo, New York 14214 and the Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut 06520

The principal feature of killing of Candida albicans and other pathogenic fungi by the catonic protein Histatin 5 (Hst 5) is loss of cytoplasmic small molecules and ions, including ATP and K⁺, which can be blocked by the anion channel inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid. We constructed C. albicans strains expressing one, two, or three copies of the TRK1 gene in order to investigate possible roles of Trk1p (the organism's principal K⁺ transporter) in the actions of Hst 5. All measured parameters (Hst 5 killing, Hst 5-stimulated ATP efflux, normal Trk1p-mediated K⁺ (⁸⁶Rb⁺) influx, and Trk1p-mediated chloride conductance) were similarly reduced (5–7-fold) by removal of a single copy of the TRK1 gene from this diploid organism and were fully restored by complementation of the missing allele. A TRK1 overexpression strain of C. albicans, constructed by integrating an additional TRK1 gene into wild-type cells, demonstrated cytoplasmic sequestration of Trk1 protein, along with somewhat diminished toxicity of Hst 5. These results could be produced either by depletion of intracellular free Hst 5 due to sequestered binding, or to cooperativity in Hst 5-protein interactions at the plasma membrane. Furthermore, Trk1p-mediated chloride conductance was blocked by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid in all of the tested strains, strongly suggesting that the TRK1 protein provides the essential pathway for ATP loss and is the critical effector for Hst 5 toxicity in C. albicans.

Received for publication, September 24, 2004 , and in revised form, October 12, 2004.

^* This work was supported by NIDCR, National Institutes of Health (NIH), Grants DE10641 and DE00406 (to M. E.) and NIGMS, NIH, Grant GM-60696 (to C. L. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: 310 Foster Hall, SUNY at Buffalo Main Street Campus, 3435 Main St., Buffalo, NY 14214. Tel.: 716-829-3067; Fax: 716-829-3942; E-mail: edgerto{at}buffalo.edu.

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