Why the study?
The functional relevance of the crosstalk between Ca2+- and voltage-sensing mechanisms on BK channel gating remains debated.
Ca2+ binding to a single α-subunit of BK channels affects all voltage-sensing domains equally, with RCK1 and RCK2 high-affinity sites contributing equally to decrease the free energy necessary for VSD activation.
Clarifies BK channel allosteric coupling; leaves open cardiovascular therapeutic translation.
Allosteric interplays between voltage-sensing domains (VSD), Ca 2+ -binding sites, and the pore domain govern the Ca 2+ - and voltage-activated K + (BK) channel opening. However, the functional relevance of the Ca 2+ - and voltage-sensing mechanisms crosstalk on BK channel gating is still debated. We examined the energetic interaction between Ca 2+ binding and VSD activation measuring and analyzing the effects of internal Ca 2+ on BK channels gating currents. Our results indicate that the Ca 2+ sensors occupancy has a strong impact on the 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, appear to 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.
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Lorenzo et al. (2019) studied this question.
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