Deconstructing voltage sensor function and pharmacology in sodium channels

Abstract

Voltage-activated sodium (Nav) channels are crucial for the generation and propagation of nerve impulses, and as such are amongst the most widely targeted ion channels by toxins and drugs. The four voltage sensors in Nav channels have distinct amino acid sequences, raising fundamental questions about their relative contributions to the function and pharmacology of the channel. Here we use four-fold symmetric voltage-activated potassium (Kv) channels as reporters to examine the contributions of individual Nav channel S3b-S4 paddle motifs to the kinetics of voltage sensor activation and to forming toxin receptors. Our results uncover binding sites for toxins from tarantula and scorpion venom on each of the four paddle motifs in Nav channels and reveal how paddle-specific interactions can be used to reshape Nav channel activity. One paddle motif is unique in that it slows voltage sensor activation and toxins selectively targeting this motif impede Nav channel inactivation. This reporter approach and the principles that emerge will be useful in developing new drugs for treating pain and Nav channelopathies.

Discovery of a selective Na V 1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

“…Similar to the effect of protoxin-II on rat DRG neurons, Ssm6a shifted the conductance-voltage relationship in a depolarizing direction (19). Ssm6a shifted the conductance-voltage relationship about +10.7, +12.9, +9.55, and +13.5 mV for hNa V 1.1, hNa V 1.2, hNa V 1.6, and hNa V 1.7, respectively (Fig.…”

Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells

“…This library could be engineered from the terrific variety of potent, VGIC subtype-selective VSTs that are increasingly being discovered. Examples of VSTs from spiders include ω-Agatoxin-IVA, which binds P-type Ca 2+ channels (58) and the ProTx-I and -II peptides, which bind Na + channel subtypes (59)(60)(61)(62), and heteropodatoxins, which bind Kv4 channels (63). The library of known VSTs is growing rapidly as venom peptides and mRNAs of more predatory animals are sequenced (64).…”

Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1

“…The drug effect on voltage-sensor movement may involve a direct targeting of the voltage-sensor or an indirect effect, due to an alteration of the lipid surrounding. [7][8][9][10] Tetraphenylporphyrin derivatives have been developed as a new class of synthetic ligands for potassium channels. 11 These water-soluble ligands have 4-fold symmetry and were designed to interact simultaneously with all 4 subunits of the tetrameric Kv channel to mimic the action of toxins that target the extracellular entrance of the Kv channel pore.…”