The depolarisation activated human ether à go-go (hEAG) potassium channels are primarily expressed in neuronal tissue but their appearance in various tumour entities is also indicative of an oncogenic role. Because upregulation of hEAG channels may yield to an enhanced cell proliferation, interventions increasing hEAG1 currents may serve similar purposes. We therefore investigated the effects of polyunsaturated fatty acids on hEAG1 channels. Arachidonic acid (AA) lowered their activation threshold, accelerated the activation kinetics and increased the open probability with a half-maximal concentration of about 4 microM. This effect correlated with the number of double bonds (db) in the fatty acids, increasing from oleic acid (1 db), linolenic acid (3 db), AA (4 db) to eicosapentaenoic acid (5 db). Unlike other voltage-gated K(+) channels, hEAG1 channels are not blocked by arachidonic acid. Therefore, in particular at typical resting potentials of tumour cells (-30 mV), AA potently activated hEAG1 channels in a reversible manner. Proliferation and metabolic activity of hEAG1-expressing human melanoma cells increased when cells were exposed to AA concentrations of 5 microM and this effect was suppressed in the presence of the hEAG1 blocker LY97241 suggesting that the proliferative effect of AA is in part mediated by activation of hEAG channels.