Co-dependent regulation of p-BRAF and potassium channel KCNMA1 levels drives glioma progression

Abstract

BRAF mutations have been found in gliomas which exhibit abnormal electrophysiological activities, implying their potential links with the ion channel functions. In this study, we identified the Drosophila potassium channel, Slowpoke (Slo), the ortholog of human KCNMA1, as a critical factor involved in dRafGOF glioma progression. Slo was upregulated in dRafGOF glioma. Knockdown of slo led to decreases in dRafGOF levels, glioma cell proliferation, and tumor-related phenotypes. Overexpression of slo in glial cells elevated dRaf expression and promoted cell proliferation. Similar mutual regulations of p-BRAF and KCNMA1 levels were then recapitulated in human glioma cells with the BRAF mutation. Elevated p-BRAF and KCNMA1 were also observed in HEK293T cells upon the treatment of 20 mM KCl, which causes membrane depolarization. Knockdown KCNMA1 in these cells led to a further decrease in cell viability. Based on these results, we conclude that the levels of p-BRAF and KCNMA1 are co-dependent and mutually regulated. We propose that, in depolarized glioma cells with BRAF mutations, high KCNMA1 levels act to repolarize membrane potential and facilitate cell growth. Our study provides a new strategy to antagonize the progression of gliomas as induced by BRAF mutations.

Transcriptomics reveals age-related changes in ion transport–related factors in yak lungs

“…KCNC3, KCNQ3, and KCNMA1 are voltage-gated potassium ion channel proteins, and the downregulation of KCNC3 and KCNQ3 in yak lungs suggested that the expression of voltage-gated potassium ion channels decreases in yaks with age, reducing membrane depolarization and harmful effects of pulmonary edema ( 29 , 30 ). KCNMA1 upregulation might be associated with its role in promoting vascular endothelial cell growth ( 31 , 32 ). SLC12A2, SLC12A4, SLC12A7, SLC4A9, SLC26A7, SLC26A4, and SLC26A9, which are SLC12A, SLC4A, and SLC26A family proteins, are cation-coupled chloride cotransporter proteins.…”

The BK Channel Limits the Pro-Inflammatory Activity of Macrophages

“…The BK channel is well known for its role in the regulation of neurotransmitter release [14][15][16] and smooth muscle contractility [17,18]. The BK channel has also been implicated in the regulation of tumor cell proliferation [19][20][21], gene expression [22], airway inflammation [23,24], hormone secretion [25,26], and cell volume [27]. Furthermore, it is considered a promising therapeutic target for hearing loss [28].…”