Sky1p and Ptk2p are protein kinases that regulate ion transport across the plasma membrane of Saccharomyces cerevisiae. We show here that deletion of SKY1 or PTK2 in trk1,2Delta cells increase spermine tolerance, implying Trk1,2p independent activity. Unexpectedly, trk1,2Deltasky1Delta and trk1,2Deltaptk2Delta cells display hypersensitivity to LiCl. These cells also show increased tolerance to low pH and improved growth in low K+, as demonstrated for deletion of PMP3 in trk1,2Delta cells. We show that Sky1p and Pmp3p act in different pathways. Hypersensitivity to LiCl and improved growth in low K+ are partly dependent on the Nha1p and Kha1p antiporters and on the Tok1p channel. Finally, Dhh1p, a RNA helicase was demonstrated to improve growth of trk1,2Deltasky1Delta cells in low K+. Overexpression of Dhh1p improves the ability of trk1,2Delta cells to grow in low K+ while dhh1Delta cells are sensitive to spermine and salt ions. A model that integrates these results to explain the mechanism of ion transport across the plasma membrane is proposed. (C) 2002 Elsevier Science (USA). All rights reserved.