Calcium-activated K + channels increase cell proliferation independent of K + conductance

Joanne E. Millership, Daniel C. Devor, Kirk L. Hamilton, Corina M. Balut, Jason I E Bruce, Ian M. Fearon

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The intermediate-conductance calcium-activated potassium channel (IK1) promotes cell proliferation of numerous cell types including endothelial cells, T lymphocytes, and several cancer cell lines. The mechanism underlying IK1-mediated cell proliferation was examined in human embryonic kidney 293 (HEK293) cells expressing recombinant human IK1 (hIK1) channels. Inhibition of hIK1 with TRAM-34 reduced cell proliferation, while expression of hIK1 in HEK293 cells increased proliferation. When HEK293 cells were transfected with a mutant (GYG/AAA) hIK1 channel, which neither conducts K + ions nor promotes Ca 2+ entry, proliferation was increased relative to mock-transfected cells. Furthermore, when HEK293 cells were transfected with a trafficking mutant (L18A/L25A) hIK1 channel, proliferation was also increased relative to control cells. The lack of functional activity of hIK1 mutants at the cell membrane was confirmed by a combination of whole cell patch-clamp electrophysiology and fura-2 imaging to assess storeoperated Ca 2+ entry and cell surface immunoprecipitation assays. Moreover, in cells expressing hIK1, inhibition of ERK1/2 and JNK kinases, but not of p38 MAP kinase, reduced cell proliferation. We conclude that functional K + efflux at the plasma membrane and the consequent hyperpolarization and enhanced Ca 2+ entry are not necessary for hIK1-induced HEK293 cell proliferation. Rather, our data suggest that hIK1-induced proliferation occurs by a direct interaction with ERK1/2 and JNK signaling pathways. © 2011 the American Physiological Society.
    Original languageEnglish
    Pages (from-to)C792-C802
    JournalAmerican Journal of Physiology: Cell Physiology
    Volume300
    Issue number4
    DOIs
    Publication statusPublished - Apr 2011

    Keywords

    • Ca 2+ influx
    • Cell proliferation
    • Intermediate conductance calcium-activated potassium channel
    • Mitogen-activated protein kinase

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