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Malignant gliomas are highly invasive brain cancers that carry a dismal prognosis. Recent studies indicate that Cl⁻ channels facilitate glioma cell invasion by promoting hydrodynamic cell shape and volume changes. Here we asked how Cl⁻ channels are regulated in the context of migration. Using patch-clamp recordings we show Cl⁻ currents are activated by physiological increases of [Ca²⁺]_i to 65 and 180nM. Cl⁻ currents appear to be mediated by ClC-3, a voltage-gated, CaMKII-regulated Cl⁻ channel highly expressed by glioma cells. ClC-3 channels colocalized with TRPC1 on caveolar lipid rafts on glioma cell processes. Using perforated-patch electrophysiological recordings, we demonstrate that inducible knockdown of TRPC1 expression with shRNA significantly inhibited glioma Cl⁻ currents in a Ca²⁺-dependent fashion, placing Cl⁻ channels under the regulation of Ca²⁺ entry via TRPC1. In chemotaxis …