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- W2067199085 abstract "We reported previously that naturally occurring hypokalemic periodic paralysis (HypoPP) mutations of voltage sensing arginines in domain II of the skeletal muscle sodium channel Nav1.4 produce gating pore currents at hyperpolarized membrane potentials. These small but persistent currents produce a gain-of-function that would contribute to the pathophysiology of HypoPP. Here we investigate biophysical properties of the gating pore with mutations in R2 in more detail. We confirm that Na+ currents through the gating pore can be blocked by Ba2+ and Zn2+ at mM concentrations. Block is voltage-dependent and is substantially increased by strongly negative holding potentials. Voltage-dependent block develops with kinetics consistent with preferential binding of divalent cations to the resting conformation of the voltage sensor. Trivalent cations such as Gd3+, La3+, Yb3+ block Na+ gating pore currents with higher affinity than divalents (hundreds of nM), but with much less voltage dependence. We also probed permeation through the gating pore. Currents through the Nav1.4/R2G gating pore carried by guanidinium (Gu+) are ∼25 fold larger than Na+ currents. Smaller derivatives like ethyl-guanidine also permeate through the gating pore better than sodium. Bulkier guanidine derivatives block both Na+ and Gu+ gating pore conductances at mM concentrations. Interestingly, HypoPP mutant Nav1.4/R2H, which is proton-selective in physiological saline, is also permeable to Gu+ despite its lack of permeability to monovalent alkali metal cations. The high Gu+ permeation through these gating pores is consistent with the expected favorable environment for the guanidinium side chains of the native arginine gating charges. Our studies reveal conformation-dependent divalent cation block of these HypoPP mutant gating pores, as well as block by guanidine derivatives, which may provide potential targets for therapeutically active compounds." @default.
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- W2067199085 date "2010-01-01" @default.
- W2067199085 modified "2023-09-26" @default.
- W2067199085 title "Block and Permeation of the Hypokalemic Periodic Paralysis Gating Pore In Nav1.4 Channels" @default.
- W2067199085 doi "https://doi.org/10.1016/j.bpj.2009.12.1689" @default.
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