Functional roles of voltage-gated potassium channels in the nucleus

Abstract

It is widely known that voltage-gated potassium (Kv) channels play a crucial role in the transmission of electrical signals by regulating the potassium that passes through the plasma membrane in excitable cells, such as neurons and cardiac muscle cells. However, recent studies have reported that several Kv channel subunits, including Kv1.3, influence cell proliferation in non-excitable cancer cells. Herein, Kv1.3 was detected at the nuclear membrane of A549 cancer cells. The effect of nuclear membrane potential with Kv1.3 selective inhibition was changed by collapse in the potassium gradient in isolated nuclei of A549 cells. The membrane-permeable Kv1.3 blocker, PAP-1, was shown to induce the phosphorylation of the cAMP response element-binding (CREB) protein and c-Fos activation in A549 cells. Chromatin immunoprecipitation assay revealed that the Sp1 transcription factor is directly bound to the promoter region of the Kv1.3 gene, and Sp1 regulated Kv1.3 expression in the nucleus of A549 cells. Furthermore, nuclear Kv1.3 was shown to form complexes with nuclear proteins including UBF1. The amino-acid sequence-based predictors demonstrated putative subcellular localization and functional domains of Kv channels and the location of Kv channels was confirmed in A549, MCF7, K562 cells, and human brain tissues using subcellular protein fractionation. These results demonstrate that nuclear Kv channels could be associated with proliferation of cancer cells by regulating nuclear membrane potential and specific transcription factors such as pCREB and c-Fos. Moreover, nuclear Kv1.3 channels mediated with Sp1 transcription factor may have unknown biological function through interaction of nuclear proteins.