title: Calcium entry via TRPC1 channels activates chloride currents in human glioma cells.
abstract: 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 [Ca(2+)]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 Ca(2+)-dependent fashion, placing Cl(-) channels under the regulation of Ca(2+) entry via TRPC1. In chemotaxis assays epidermal growth factor (EGF)-induced invasion was inhibition by TRPC1 knockdown to the same extent as pharmacological block of Cl(-) channels. Thus endogenous glioma Cl(-) channels are regulated by TRPC1. Cl(-) channels could be an important downstream target of TRPC1 in many other cells types, coupling elevations in [Ca(2+)]i to the shape and volume changes associated with migrating cells.
authors.affiliation: Department of Neurobiology and Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Vishnu Anand
authors.initials: VA
authors.lastname: Cuddapah
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Turner
authors.forename: Harald
authors.initials: H
authors.lastname: Sontheimer
mesh_terms: D002118:Calcium / Q000378:metabolism*; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D004553:Electric Conductivity; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: D018118:Chloride Channels; D002712:Chlorides; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D002118:Calcium