The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

Abstract

Although necessary for human survival, pain may sometimes become pathologic if long-lasting and associated with alterations in its signaling pathway. Opioid painkillers are officially used to treat moderate to severe, and even mild, pain. However, the consequent strong and not so rare complications that occur, including addiction and overdose, combined with pain management costs, remain an important societal and economic concern. In this context, animal venom toxins represent an original source of antinociceptive peptides that mainly target ion channels (such as ASICs as well as TRP, Ca_V, K_V and Na_V channels) involved in pain transmission. The present review aims to highlight the Na_V1.7 channel subtype as an antinociceptive target for spider toxins in adult dorsal root ganglia neurons. It will detail (i) the characteristics of these primary sensory neurons, the first ones in contact with pain stimulus and conveying the nociceptive message, (ii) the electrophysiological properties of the different Na_V channel subtypes expressed in these neurons, with a particular attention on the Na_V1.7 subtype, an antinociceptive target of choice that has been validated by human genetic evidence, and (iii) the features of spider venom toxins, shaped of inhibitory cysteine knot motif, that present high affinity for the Na_V1.7 subtype associated with evidenced analgesic efficacy in animal models.

Keywords: NaV1.7 channel subtype; dorsal root ganglia neurons; electrophysiology; pain; spider toxins; voltage-gated sodium channels.

FIGURE 1

Cellular elements involved in pain transmission from the peripheral to the central nervous system (CNS). (Box 1) The pain (thermal, high pressure, mechanical, chemical) information is first detected by the receptors located at the level of free nerve endings of primary sensory neuron (PSN) fibers. (Box 2) Then, it is conveyed by the dendrites of these neurons, components of dorsal root ganglia (DRG), to the dorsal horn of spinal cord where it is transmitted to the dendrites of secondary sensory neurons (SSNs). (Box 3) Finally, it is brought to the hypothalamus via the tertiary sensory neurons (TSNs) whose cell bodies constitute, in part, the brain cortex.

FIGURE 2

Schematic representation of morphological characteristics of ganglion and nerve capillaries. Ganglion capillaries differ from nerve ones by the presence of fenestration and absence of narrow tight junctions. Nerve endothelial cells are surrounded by pericytes.

FIGURE 3

The voltage-gated sodium channel. Schematic representations of α-subunit and auxiliary β-subunit of Na_V channels, in which cylinders are transmembrane α helices. In red: S5 and S6 pore-forming segments, in green: S4 voltage-sensor segment, and in blue: S1, S2, and S3 segments. IFM, isoleucine, phenylalanine and methionine residues. The orange loops in DII and DIV domains correspond to spider toxins binding sites (adapted from Catterall et al., 2007).

FIGURE 4

Relative proportion of Na_V channel α-subunits detected in mammalian dorsal root ganglia (DRG) neurons by RT-PCR. DRG neurons are from some representative mammals of different orders reported in the literature: primates, artyodactyla and rodents. The first order, including human and monkey, is closely related to the pig, belonging to the second order. The rodents, more distant from the human, represent the model often used for pain studies. The adult post-mortem human DRG neurons were obtained from healthy donors. All the data are from DRG neurons of adult mammals except those from 7 day-old rats. ND, non-determined. Adapted from Raymond et al. (2004), Berta et al. (2008), Ho and O’Leary (2011), Muroi and Undem (2014), and Chang et al. (2018).

FIGURE 5

Sequence alignment obtained by Multalin (version 5.4.1) of different potential analgesic toxins sorted by Na_V spider toxins families, using their UniProtKB identifiers. The consensus sequence is shown above each alignment, with the disulfide bond connectivity. In dark blue, highly conserved amino acid residues (100%), and in light blue, poorly conserved amino acid residues (>50%). The Greek letter(s) before the toxin name is associated to its type of action: μ for Na_V channel inhibition, β for shift in the voltage-dependence of Na_V channel activation, ω for Ca_V channel inhibition, and κ for K_V channel inhibition. ProTx, protoxin; HnTx, hainantoxin; CcoTx, ceratotoxin; HwTx, huwentoxin; JzTx, jingzhaotoxin; aa, amino acid residues; NaSpTx, spider Na_V channel toxin.