α-Actinin-2 couples to cardiac Kv1.5 channels, regulating current density and channel localization in HEK cells

Voltage-gated K + (Kv) channels are particularly important in the physiology of excitable cells in the heart and the brain. PSD-95 is known to cluster Shaker channels and NMDA receptors and the latter is known to couple through α-actinin-2 to the post-synaptic cytoskeleton [Wyszynski et al. (1997) Nature 385, 439–442], but the mechanisms by which Kv channels are linked to the actin cytoskeleton and clustered at specific sites in the heart are unknown. Here we provide evidence that Kv1.5 channels, widely expressed in the cardiovascular system, bind with α-actinin-2. Human Kv1.5 interacts via its N-terminus/core region and can be immunoprecipitated with α-actinin-2 both after in vitro translation and from HEK cells expressing both proteins. The ion channels and α-actinin-2 co-localize at the membrane in HEK cells, where disruption of the actin cytoskeleton and antisense constructs to α-actinin-2 modulate the ion and gating current density.