The molecular basis of pH sensing by the human fungal pathogen Candida albicans TOK potassium channel
Rían W. Manville,
Claire L. Illeck,
Anthony Lewis,
Zoe A. McCrossan,
Steven A.N. Goldstein,
Geoffrey W. Abbott
Affiliations
Rían W. Manville
Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
Claire L. Illeck
Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
Anthony Lewis
School of Medicine, Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT Hants, UK
Zoe A. McCrossan
NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC), University of Southampton, Southampton, SO16 7NS Hampshire, UK
Steven A.N. Goldstein
Departments of Physiology & Biophysics, Pediatrics, and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, Irvine, CA 92697, USA
Geoffrey W. Abbott
Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Corresponding author
Summary: Two-pore domain, outwardly rectifying potassium (TOK) channels are exclusively expressed in fungi. Human fungal pathogen TOK channels are potential antifungal targets, but TOK channel modulation in general is poorly understood. Here, we discovered that Candida albicans TOK (CaTOK) is regulated by extracellular pH, in contrast to TOK channels from other fungal species tested. Low pH increased CaTOK channel outward currents (pKa = 6.0), hyperpolarized the voltage-dependence of TOK activation, and increased pore selectivity for K+ over Na+, shifting the reversal potential (EREV) toward EK. Mutating H144 in the S1-S2 extracellular linker partially diminished pH sensitivity, suggesting H144 forms part of the CaTOK pH sensor. Functional analysis of chimeras made with pH-insensitive Saccharomyces cerevisiae TOK and point mutants revealed that CaTOK V462 and S466 in the final transmembrane segment complete the pH-responsive elements. A tripartite network of residues thus endows CaTOK with the ability to respond functionally to changes in pH.
