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

Allosteric interactions between the voltage-sensing domain (VSD), the Ca(2+)-binding sites, and the pore domain govern the mammalian Ca(2+)- and voltage-activated K(+) (BK) channel opening. However, the functional relevance of the crosstalk between the Ca(2+)- and voltage-sensing mechanisms on BK channel gating is still debated. We examined the energetic interaction between Ca(2+) binding and VSD activation by investigating the effects of internal Ca(2+) on BK channel gating currents. Our results indicate that Ca(2+) sensor occupancy has a strong impact on VSD activation through a coordinated interaction mechanism in which Ca(2+) binding to a single α-subunit affects all VSDs equally. Moreover, the two distinct high-affinity Ca(2+)-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 Ca(2+) sensors and VSDs.