pH Modulation of Voltage-Gated Sodium Channels
Colin H Peters1, Mohammad-Reza Ghovanloo1, Cynthia Gershome1
1Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
Handbook of Experimental Pharmacology
|February 21, 2018
Summary
Changes in blood pH affect sodium channels, potentially triggering electrical disease symptoms in patients with mutations. Protons alter channel function, impacting current amplitude and persistence, especially in sensitive mutants.
Area of Science:
- Physiology
- Molecular Biology
- Pathophysiology
Background:
- Blood and tissue pH changes occur during physiological and pathophysiological states like exercise, ischemia, and drug use.
- These pH shifts are implicated in triggering electrical disease symptoms in individuals with sodium channel mutations.
- Protons (H+) significantly impact sodium channel gating, affecting ion current amplitude and channel inactivation.
Purpose of the Study:
- To review the mechanisms of proton block within the sodium channel pore.
- To explore proposed mechanisms by which protons influence sodium channel gating.
- To discuss isoform specificity, tissue-level effects, and the role of protons in disease, including studies on proton-sensitizing mutants.
Main Methods:
- Literature review of proton effects on sodium channels.
- Analysis of existing data on proton block and gating modulation.
- Examination of studies on proton-sensitizing mutants in cardiac and skeletal muscle sodium channels.
Main Results:
- Protons generally decrease transient sodium current amplitude.
- Protons increase the proportion of non-inactivating sodium channels, leading to persistent currents.
- Proton effects are observed across neuronal, skeletal, and cardiac sodium channel isoforms, with varying sensitivity.
Conclusions:
- Proton-induced alterations in sodium channel function may contribute to acute electrical disease symptoms.
- Mutations that increase proton sensitivity can exacerbate these effects.
- Understanding proton interactions with sodium channels is crucial for comprehending electrical diseases.
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