A Tale of Two Residues: Exploring Novel Hypokalemic Periodic Paralysis Sodium Channel Mutations K1126I and R1129Q
Faculty Mentor Information
Dr. James Groome (Mentor), Idaho State University
Abstract
A difference in membrane potential dictates the electrical signal across a cell membrane, and its dysfunction is observed in diseases of neural and muscle cells. Hypokalemic periodic paralysis is a hypoexcitable skeletal muscle disorder in which patients experience attacks of muscle paralysis. This state of paralysis is associated with mutations of the human voltage-gated sodium (Nav) channel. Two novel periodic paralysis mutants within the S4 segment of domain III in the channel, K1126I and R1129Q, have not yet been studied. Here, we determined the impact of these mutations on channel function using cut open oocyte voltage clamp (COVC) electrophysiology. To compare wild type and mutant channels, Xenopus oocytes were injected with the desired messenger RNA. A series of protocols were employed to analyze the impact of mutations on the sodium channel. These included probability of activation and inactivation, and kinetics of deactivation, entry into inactivation, and recovery from inactivation. Our findings suggest that these mutations enhance inactivation to produce hypoexcitability in muscle fiber. In the future, we will use double cysteine mutations to investigate interactions of K1126 and R1129 with other DIII residues that we hypothesize are disrupted by the S4 mutations.
A Tale of Two Residues: Exploring Novel Hypokalemic Periodic Paralysis Sodium Channel Mutations K1126I and R1129Q
A difference in membrane potential dictates the electrical signal across a cell membrane, and its dysfunction is observed in diseases of neural and muscle cells. Hypokalemic periodic paralysis is a hypoexcitable skeletal muscle disorder in which patients experience attacks of muscle paralysis. This state of paralysis is associated with mutations of the human voltage-gated sodium (Nav) channel. Two novel periodic paralysis mutants within the S4 segment of domain III in the channel, K1126I and R1129Q, have not yet been studied. Here, we determined the impact of these mutations on channel function using cut open oocyte voltage clamp (COVC) electrophysiology. To compare wild type and mutant channels, Xenopus oocytes were injected with the desired messenger RNA. A series of protocols were employed to analyze the impact of mutations on the sodium channel. These included probability of activation and inactivation, and kinetics of deactivation, entry into inactivation, and recovery from inactivation. Our findings suggest that these mutations enhance inactivation to produce hypoexcitability in muscle fiber. In the future, we will use double cysteine mutations to investigate interactions of K1126 and R1129 with other DIII residues that we hypothesize are disrupted by the S4 mutations.