The mechanism of inward rectification in Kir channels: A novel kinetic model with non-equilibrium thermodynamics approach

•“Driving force”-dependent block in Kir channels is simulated with a kinetic model.•The “steep voltage dependence” near EK is due to flux-dependent block.•The single-file multi-ion cytoplasmic pore is essential for flux coupling.•The flux-dependent block can be demonstrated by concentration gradient alone.•Fluctuation theorem in small systems is applied to explain the flux ratio.

The mechanisms of the strong inward rectification in inward rectifier K+ (Kir) channels are controversial because the drop in electrical potential due to the movement of the blocker and coupling ions is insufficient to explain the steep voltage-dependent block near the equilibrium potential. Here, we study the “driving force”-dependent block in Kir channels with a novel approach incorporating concepts from the non-equilibrium thermodynamics of small systems, and computer kinetic simulations based on the experimental data of internal Ba2 + block on Kir2.1 channels. The steep exponential increase in the apparent binding rate near the equilibrium potential is explained, when the encounter frequency is construed as the likelihood of transfer events down or against the electrochemical potential gradient. The exponent of flux ratio, nf = 2.62, implies that the blockage of the internal blocker may be coupled with the outward transport of 2 to 3 K+ ions. The flux-coupled block in the single-file multi-ion pore can be demonstrated by the concentration gradient alone, as well as when the driving force is the electrochemical potential difference across the membrane.

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