Calcium-driven regulation of voltage-sensing domains in BK channels.

Abstract

Allosteric interactions between the voltage-sensing domain (VSD), the Ca²⁺-binding sites, and the pore domain govern the mammalian Ca²⁺- and voltage-activated K⁺ (BK) channel opening. However, the functional relevance of the crosstalk between the Ca²⁺- and voltage-sensing mechanisms on BK channel gating is still debated. We examined the energetic interaction between Ca²⁺ binding and VSD activation by investigating the effects of internal Ca²⁺ on BK channel gating currents. Our results indicate that Ca²⁺ sensor occupancy has a strong impact on VSD activation through a coordinated interaction mechanism in which Ca²⁺ binding to a single α-subunit affects all VSDs equally. Moreover, the two distinct high-affinity Ca²⁺-binding sites contained in the C-terminus domains, RCK1 and RCK2, contribute equally to decrease the free energy necessary to activate the VSD. We conclude that voltage-dependent gating and pore opening in BK channels is modulated to a great extent by the interaction between Ca²⁺ sensors and VSDs.