Low-dose photon irradiation alters cell differentiation via activation of hIK channels

To understand the impact of ionizing irradiation from diagnostics and radiotherapy on cells, we examined K⁺ channel activity before and immediately after exposing cells to X-rays. Already, low dose in the cGy range caused in adenocarcinoma A549 cells within minutes a hyperpolarization following activation of the human intermediate-conductance Ca²⁺-activated K⁺ channel (hIK). The response was specific for cells, which functionally expressed hIK channels and in which hIK activity was low before irradiation. HEK293 cells, which do not respond to X-ray irradiation, accordingly develop a sensitivity to this stress after heterologous expression of hIK channels. The data suggest that hIK activation involves a Ca²⁺-mediated signaling cascade because channel activation is suppressed by a strong cytosolic Ca²⁺ buffer. The finding that an elevation of H2O2 causes an increase in the concentration of cytosolic Ca²⁺ suggests that radicals, which emerge early in response to irradiation, trigger this Ca²⁺ signaling cascade. Inhibition of hIK channels by specific blockers clotrimazole and TRAM-34 slowed cell proliferation and migration in "wound" scratch assays; ionizing irradiation, in turn, stimulated the latter process presumably via its activation of the hIK channels. These data stress an indirect radiosensitivity of hIK channels with an impact on cell differentiation.