Functional coupling of intracellular calcium and inactivation of voltage-gated Kv1.1/Kvbeta1.1 A-type K+ channels.

Voltage-gated Kv1.1/Kvbeta1.1 A-type channels, as a natural complex, can switch from fast to slow inactivation under oxidation/reduction conditions. The mode-switching of inactivation, which is mediated by a cysteine residue in the inactivation ball domain of the Kvbeta1.1 N terminus, can regulate membrane electrical excitability. In the present study, we identified a mechanism whereby inactivation in Kv1.1/Kvbeta1.1 channels is regulated by calcium influx. The rise in intracellular calcium, due to either influx from extracellular space or release from intracellular stores, eliminates fast inactivation induced by Kvbeta1.1, resulting in slower inactivation and increased steady-state current. This oxidation-independent calcium effect is mediated through the Kvbeta1.1 N terminus, not the C terminus. We propose that a coupling between calcium influx and inactivation of voltage-gated A-type K+ channels occurs as a result of membrane depolarization and may contribute to afterhyperpolarization as negative feedback to control neuronal excitability.

Two N-terminal domains of Kv4 K(+) channels regulate binding to and modulation by KChIP1.

The family of calcium binding proteins called KChIPs associates with Kv4 family K(+) channels and modulates their biophysical properties. Here, using mutagenesis and X-ray crystallography, we explore the interaction between Kv4 subunits and KChIP1. Two regions in the Kv4.2 N terminus, residues 7-11 and 71-90, are necessary for KChIP1 modulation and interaction with Kv4.2. When inserted into the Kv1.2 N terminus, residues 71-90 of Kv4.2 are also sufficient to confer association with KChIP1. To provide a structural framework for these data, we solved the crystal structures of Kv4.3N and KChIP1 individually. Taken together with the mutagenesis data, the individual structures suggest that that the Kv4 N terminus is required for stable association with KChIP1, perhaps through a hydrophobic surface interaction, and that residues 71-90 in Kv4 subunits form a contact loop that mediates the specific association of KChIPs with Kv4 subunits.