title: Physical and functional interactions between a glioma cation channel and integrin-β1 require α-actinin.
abstract: Major plasma membrane components of the tumor cell, ion channels, and integrins play crucial roles in metastasis. Glioma cells express an amiloride-sensitive nonselective cation channel composed of acid-sensing ion channel (ASIC)-1 and epithelial Na(+) channel (ENaC) α- and γ-subunits. Inhibition of this channel is associated with reduced cell migration and proliferation. Using the ASIC-1 subunit as a reporter for the channel complex, we found a physical and functional interaction between this channel and integrin-β1. Short hairpin RNA knockdown of integrin-β1 attenuated the amiloride-sensitive current, which was due to loss of surface expression of ASIC-1. In contrast, upregulation of membrane expression of integrin-β1 increased the surface expression of ASIC-1. The link between the amiloride-sensitive channel and integrin-β1 was mediated by α-actinin. Downregulation of α-actinin-1 or -4 attenuated the amiloride-sensitive current. Mutation of the putative binding site for α-actinin on the COOH terminus of ASIC-1 reduced the membrane localization of ASIC-1 and also resulted in attenuation of the amiloride-sensitive current. Our data suggest a novel interaction between the amiloride-sensitive glioma cation channel and integrin-β1, mediated by α-actinin. This interaction may form a mechanism by which channel activity can regulate glioma cell proliferation and migration.
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rooj
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: McNicholas
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Fuller
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology
chemical_list: C568266:ASIC1 protein, human; D062565:Acid Sensing Ion Channels; D000199:Actins; D019012:Integrin beta1
keywords: ASIC-1; Deg/ENaC; amiloride; cytoskeleton