Modulation of A-type potassium channels by a family of calcium sensors

In the brain and heart, rapidly inactivating (A-type) voltage-gated potassi um (Kv) currents operate at subthreshold membrane potentials to control the excitability of neurons and cardiac myocytes(1,2). Although pore-forming a lpha-subunits of the Kv4, or Shal-related, channel family form A-type curre nts in heterologous cells(3), these differ significantly from native A-type currents. Here we describe three Kv channel-interacting proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 alpha-subunits. We find t hat expression of KChIP and Kv4 together reconstitutes several features of native A-type currents by modulating the density, inactivation kinetics and rate of recovery from inactivation of Kv4 channels in heterologous cells. All three KChIPs co-localize and co-immunoprecipitate with brain Kv4 alpha- subunits, and are thus integral components of native Kv4 channel complexes. The KChIPs have four EF-hand-like domains and bind calcium ions. As the ac tivity and density of neuronal A-type currents tightly control responses to excitatory synaptic inputs, these KChIPs may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calci um.