Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels play an important role in the regulation of cell physiology in a wide variety of excitable and nonexcitable tissues. Filamin A is a conserved and ubiquitous actin-binding protein that forms perpendicular actin cross-links and contributes to changes in cell shape, stiffness, and motility. A variety of membrane proteins bind to filamin A, which regulates their trafficking in and out of the plasma membrane. Filamin A is therefore believed to couple membrane dynamics with those of the underlying cytoskeleton. Filamin A was identified in a yeast two-hybrid screen of a neuronal transcriptome using a subunit of BK(Ca) channels as bait, and the interaction was confirmed by a variety of biochemical assays in native neuronal cells and in human embryonic kidney 293T cells expressing BK(Ca) channels. BK(Ca) channels do not traffic to the plasma membrane in M2 melanoma cells, which lack filamin A, but normal trafficking is seen in A7 cells, which express filamin A, or in M2 cells transiently transfected with filamin A. It is noteworthy that stimulation of plasma membrane expression of BK(Ca) channels also occurs when M2 cells are transfected with filamin A constructs that lack the actin binding domain and that do not bind actin in vivo or in vitro. Filamin A is necessary for normal trafficking of BK(Ca) channels to the plasma membrane, but this effect does not require interactions with actin microfilaments, and it is possible that other actions of the filamin family of scaffolding proteins are independent of effects on actin.