Calcium-dependent electrostatic control of anion access to the pore of the calcium-activated chloride channel TMEM16A

Calcium-dependent electrostatic control of anion access to the pore of the calcium-activated chloride channel TMEM16A

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TMEM16A is a ligand-gated anion channel that is activated by intracellular Ca2+.This channel comprises two independent pores and closely apposed Ca2+ binding sites that are contained within each subunit Sugar Bowls of a homodimeric protein.Previously we characterized the influence of positively charged pore-lining residues on anion conduction (Paulino et al., 2017a).Here, we demonstrate the electrostatic control of permeation by the bound calcium ions in mouse TMEM16A using electrophysiology and Poisson-Boltzmann calculations.

The currents of constitutively active mutants lose their outward rectification as a function of Ca2+ concentration due Normally Open Thermal Cutout to the alleviation of energy barriers for anion conduction.This phenomenon originates from Coulombic interactions between the bound Ca2+ and permeating anions and thus demonstrates that an electrostatic gate imposed by the vacant binding site present in the sterically open pore, is released by Ca2+ binding to enable an otherwise sub-conductive pore to conduct with full capacity.