Abstract
Eukaryotic voltage-gated sodium channels play key roles in physiology and are targets for many toxins and medically important drugs. Physiology, pharmacology, and general architecture of the channels has long been the subject of intensive research in academia and industry. In particular, animal toxins such as tetrodotoxin, saxitoxin, and conotoxins have been used as molecular probes of the channel structure. More recently, X-ray structures of potassium and prokaryotic sodium channels allowed elaborating models of the toxin-channel complexes that integrated data from biophysical, electrophysiological, and mutational studies. Atomic level cryo-EM structures of eukaryotic sodium channels, which became available in 2017, show that the selectivity filter structure and other important features of the pore domain have been correctly predicted. This validates further employments of toxins and other small molecules as sensitive probes of fine structural details of ion channels.
Highlights
Voltage-gated sodium channels belong to the superfamily of voltage-gated ion channels, which include calcium, potassium, glutamate-gated, and other channels
After prolonged membrane depolarization, voltage-gated sodium channels (VGSCs) enter into slow-inactivated states, the process important for regulating membrane excitability, action potential patterns, and spike frequency adaptation (Vilin and Ruben, 2001; Ulbricht, 2005)
Action of these small semi-rigid toxins on VGSCs is reviewed by many authors (e.g., Hille, 2001; Moczydlowski, 2013; Thottumkara et al, 2014)
Summary
Voltage-gated sodium channels belong to the superfamily of voltage-gated ion channels, which include calcium, potassium, glutamate-gated, and other channels. Segments S1–S4 form VSDs. Segments S5 (the outer helices), S6 (the inner helices), and extracellular membrane reentering P-loops between S5 and S6 contribute to the pore domain (Figure 1A). The P-loops contain membrane-descending (P1) and membrane-ascending (P2) helices with residues between P1 and P2 contributing to the selectivity filter. In eukaryotic VGSCs, the selectivity filter DEKA ring, which contains D, E, K, and A residues, borders the extracellularly exposed outer pore and the inner pore that is exposed to the cytoplasm in the open channel (Figure 1B). The activation gate, which is composed of the cytoplasmic parts of S6s, forms a tight ion-impermeable bundle in the closed state. Upon membrane depolarization the S4 helices, which contain positively charged residues, shift in the extracellular direction, inducing movements of the S4–S5 linker helices and the activation gate opening.
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