Evidence for a functional interaction between integrins and G protein-activated inward rectifier K+ channels

Heteromultimeric G protein-activated inward rectifier K+ (GIRK) channels, a bundant in heart and brain, help to determine the cellular membrane potenti al as well as the frequency and duration of electrical impulses. The sequen ce arginine-glycine aspartate (RGD), located extracellularly between the fi rst membrane-spanning region and the pore, is conserved among all identifie d GIRK subunits but is not found in the extracellular domain of any other c loned K+ channels. Many integrins, which, like channels, are integral membr ane proteins, recognize this RGD sequence on other proteins, usually in the extracellular matrix. We therefore asked whether GIRK activity might be re gulated by direct interaction with integrin, Here, we present evidence that mutation of the RGD site to RGE, particularly on the GIRK4 subunit, decrea ses or abolishes GIRK current. Furthermore, wild-type channels can be co-im munoprecipitated with integrin, The total cellular amount of expressed muta nt GIRK channel protein is the same as the wild-type protein; however, the amount of mutant channel protein that localizes to the plasma membrane is d ecreased relative to wild-type, most likely accounting for the diminished G IRK current detected. GIRK channels appear to bind directly to integrin and to require this interaction for proper GIRK channel membrane localization and function.