Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy

Abstract

Voltage-gated sodium channels initiate action potentials in brain neurons. In the 1970’s, much was known about the function of sodium channels from measurements of ionic currents using the voltage clamp method, but there was no information about the sodium channel molecules themselves. As a postdoctoral fellow and staff scientist at the National Institutes of Health, I developed neurotoxins as molecular probes of sodium channels in cultured neuroblastoma cells. During those years, Bruce Ransom and I crossed paths as members of the laboratories of Marshall Nirenberg and Philip Nelson and shared insights about sodium channels in neuroblastoma cells from my work and electrical excitability and synaptic transmission in cultured spinal cord neurons from Bruce’s pioneering electrophysiological studies. When I established my laboratory at the University of Washington in 1977, my colleagues and I used those neurotoxins to identify the protein subunits of sodium channels, purify them, and reconstitute their ion conductance activity in pure form. Subsequent studies identified the molecular basis for the main functions of sodium channels—voltage-dependent activation, rapid and selective ion conductance, and fast inactivation. Bruce Ransom and I re-connected in the 1990’s, as ski buddies at the Winter Conference on Brain Research and as faculty colleagues at the University of Washington when Bruce became our founding Chair of Neurology and provided visionary leadership of that department. In the past decade my work on sodium channels has evolved into structural biology. Molecular modeling and X-ray crystallographic studies have given new views of sodium channel function at atomic resolution. Sodium channels are also the molecular targets for genetic diseases, including Dravet Syndrome, an intractable pediatric epilepsy disorder with major co-morbidities of cognitive deficit, autistic-like behaviors, and premature death that is caused by loss-of-function mutations in the brain sodium channel NaV1.1. Our work on a mouse genetic model of this disease has shown that its multi-faceted pathophysiology and co-morbidities derive from selective loss of electrical excitability and action potential firing in GABAergic inhibitory neurons, which disinhibits neural circuits throughout the brain and leads directly to the epilepsy, premature death and complex co-morbidities of this disease. It has been rewarding for me to use our developing knowledge of sodium channels to help understand the pathophysiology and to suggest potential therapeutic approaches for this devastating childhood disease.

Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels

“…The Na V 1.5 a-subunit has four homologous domains (I-IV), each with six transmembrane segments that fold to form one central ion conduction pore. Domains I and II are critical to opening the pore (activation) (Catterall, 2017;Cestè le et al, 1998Cestè le et al, , 2001. Fast inactivation results from pore occlusion by an IFM triplet of residues in the linker between domains III and IV (Vassilev et al, 1988;West et al, 1992;Cha et al, 1999).…”

Mechanistic insights into Nav1.7‐dependent regulation of rat prostate cancer cell invasiveness revealed by toxin probes and proteomic analysis

“…To date, nine Nav subtypes (Nav1.1–Nav1.9, named based on the Nav alpha subunit) have been characterized . These Navs are mainly expressed in excitable cells, such as neurons in the central/peripheral nervous system, as well as cardiac and skeletal muscle cells, and they are responsible for generating and propagating action potentials . In addition, Navs are also expressed in non‐excitable cells—including glia, fibroblasts, immune cells, and metastatic cancer cells .…”

Riluzole promotes neurological function recovery and inhibits damage extension in rats following spinal cord injury: a meta‐analysis and systematic review

“…An influx of sodium via voltage‐gated sodium channels (VGSCs) is important for maintaining neural cell excitability and regulating cellular homeostasis (Valente et al . ; Catterall ; Lindsly et al . ).…”

“…An influx of sodium via voltage-gated sodium channels (VGSCs) is important for maintaining neural cell excitability and regulating cellular homeostasis (Valente et al 2016;Catterall 2017;Lindsly et al 2017). In contrast, an excessive influx of sodium or glutamate release can induce cell toxicity (Jung et al 2013;Liu et al 2018).…”