Yenisleidy Lorenzo-CeballosWilly Carrasquel-UrsulaezOsvaldo AlvarezCastillo, KarenKarenCastilloLatorre, RamónRamónLatorre2025-04-122025-04-122019-09-0110.7554/elife.449342-s2.0-85072687063https://cris-uv-2.scimago.es/handle/123456789/1798WOS:000488039700001Allosteric 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 a-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.enacceso abiertoBiologyBiochemistry, Genetics And Molecular BiologyImmunology And MicrobiologyMedicineNeurosciencearticle