Characterization of allosteric interplay between the specialized-sensory modules in bk channel by calcium-driven regulation of voltage-sensing domains




Facultad de Ciencias

Departamento o Escuela

Facultad de Ciencias. Programa de Doctorado en Ciencias con Mención en Neurociencia.




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Doctora en Ciencias con Mención Neurociencia. Universidad de Valparaíso. 2019


A hallmark of large conductance Ca2+- and voltage-activated K+ (BK) channels is its dual regulation by two distinct physiological stimuli, intracellular Ca2+ and membrane potential. The specialized sensing modules responsible for detecting cytosolic Ca2+ elevation and membrane depolarization can act synergistically and independently allowing BK channels to operate in a wide-ranging of internal Ca2+ and voltage conditions. The functional contributions of the Ca2+ and voltage sensors to the channel opening arise from allosteric interactions propagated among three structural domains: a pore domain (PD), a voltage-sensor domain (VSD), and two Ca2+-binding sites located on non-identical regulators of conductance for K+ (RCK) domains that form a cytosolic gating ring (CTD). However, the strength of the Ca2+- and voltage sensors coupling and their functional relevance on the BK channel gating mechanism is still an unresolved matter. Using gating currents analysis, we examined the allosteric coupling between Ca2+ and voltage sensors. Our results reveal a strong energetic interplay between the voltage- and Ca2+-sensing modules through a coordinated interaction mechanism in which Ca2+ binding to a single α-subunit affects all VSDs equally. Interestingly, the two distinct Ca2+-binding sites contained in the RCK1 and RCK2 domains appear to contribute equally to decrease the free energy necessary to activate the VSDs. Some diversity in the physiological roles of BK channels is given by co-assembly of pore-forming α-subunits with tissue-specific β-subunits. Particularly, β1-subunit affect dramatically VSD function, although the biophysical and molecular mechanisms are still under debate. Preliminary results suggest that β-subunits, specifically β1- and β3b-subunits does not affect the CTD-VSD allosteric interaction. However, the presence of β1-subunit, in addition to its known effect stabilizing the active configuration of the voltage sensor, appears to decrease the extension of VSD displacement and/or to modify the membrane electric field.


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