Physical and functional interactions between a glioma cation channel and integrin-β1 require α-actinin

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) alpha- and gamma-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-beta(1). Short hairpin RNA knockdown of integrin-beta(1) attenuated the amiloride-sensitive current, which was due to loss of surface expression of ASIC-1. In contrast, upregulation of membrane expression of integrin-beta(1) increased the surface expression of ASIC-1. The link between the amiloride-sensitive channel and integrin-beta(1) was mediated by alpha-actinin. Downregulation of alpha-actinin-1 or -4 attenuated the amiloride-sensitive current. Mutation of the putative binding site for alpha-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-beta(1), mediated by alpha-actinin. This interaction may form a mechanism by which channel activity can regulate glioma cell proliferation and migration.