Abstract Astrocytes play a key role in regulating glioma cell volume, a major determinant of tumor invasiveness. We previously reported that astrocyte-derived extracellular vesicles (ADEVs) transfer microRNA miR-124 to murine glioma cells, impairing cell volume regulation and reducing the functional expression of volume-regulated anion channel (VRAC). Here, we identify the intermediate-conductance Ca 2+ -activated K + (IK) channel, the only volume-regulated K + channel acting in concert with VRAC in GL261 glioma cells, as an additional indirect target of miR-124. Mechanistically, ADEV-derived miR-124 decreases the expression of ryanodine receptor type-1 (RyR1) and inositol 1,4,5-trisphosphate receptor type-3 (IP 3 R3), the principal endoplasmic reticulum (ER) Ca 2+ release channels in these cells. This reduction in ER-mediated Ca 2+ signaling markedly decreases ERK1/2 phosphorylation and IK channel gene transcription. Consistent with these molecular effects, fetal bovine serum-induced IK channel activation, driven by ER Ca 2+ release, was strongly reduced by ADEVs and miR-124, and three-dimensional migration was impaired. Notably, combined pharmacological inhibition of IK and VRAC recapitulated the deficits in volume regulation induced by ADEVs and miR-124. Collectively, these findings show that ADEVs restrict glioma cell migration through a miR-124-dependent pathway that suppresses ER Ca 2+ release, reduces ERK1/2 activation, and diminishes IK channel expression and function. Together with our previous in vivo evidence for ADEVs- and miR-124 -mediated targeting of VRAC, these results identify coordinated regulation of K + and Cl⁻ channels as a mechanism by which astrocytes constrain glioma progression.
Catalano et al. (2026) studied this question.