Hyperkalemic periodic paralysis M1592V mutation modifies activation in human skeletal muscle Na+ channel |
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Authors: | Rojas, Cecilia V. Neely, Alan Velasco-Loyden, Gabriela Palma, Veronica Kukuljan, Manuel |
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Abstract: | Mutations in thehuman skeletal muscle Na+ channelunderlie the autosomal dominant disease hyperkalemic periodic paralysis (HPP). Muscle fibers from affected individuals exhibit sustained Na+ currents thought to depolarizethe sarcolemma and thus inactivate normalNa+ channels. We expressed humanwild-type or M1592V mutant-subunits with the 1-subunitin Xenopus laevis oocytes and recordedNa+ currents using two-electrodeand cut-open oocyte voltage-clamp techniques. The most prominentfunctional difference betweenM1592V mutant and wild-typechannels is a 5- to 10-mV shift in the hyperpolarized direction of thesteady-state activation curve. The shift in the activation curve forthe mutant results in a larger overlap with the inactivation curve thanthat observed for wild-type channels. Accordingly, the current throughM1592V channels displays a larger noninactivating component than does that through wild-type channels atmembrane potentials near 40 mV. The functional properties of theM1592V mutant resemble those ofthe previously characterized HPPT704M mutant. Both clinicallysimilar phenotypes arise from mutations located at a distance from theputative voltage sensor of the channel. |
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