Conotoxins targeting neuronal voltage-gated sodium channel subtypes: potential analgesics?

Abstract

Voltage-gated sodium channels (VGSC) are the primary mediators of electrical signal amplification and propagation in excitable cells. VGSC subtypes are diverse, with different biophysical and pharmacological properties, and varied tissue distribution. Altered VGSC expression and/or increased VGSC activity in sensory neurons is characteristic of inflammatory and neuropathic pain states. Therefore, VGSC modulators could be used in prospective analgesic compounds. VGSCs have specific binding sites for four conotoxin families: μ-, μO-, δ- and ί-conotoxins. Various studies have identified that the binding site of these peptide toxins is restricted to well-defined areas or domains. To date, only the μ- and μO-family exhibit analgesic properties in animal pain models. This review will focus on conotoxins from the μ- and μO-families that act on neuronal VGSCs. Examples of how these conotoxins target various pharmacologically important neuronal ion channels, as well as potential problems with the development of drugs from conotoxins, will be discussed.

Figure 1

Structures and sequences of analgesic μ- and μO-conotoxins. (A) Solution structures of analgesic μ-conotoxins, KIIIA and SIIIA. Disulfide links (green) with critical lysine (cyan, K7 (KIIIA) and K11 (SIIIA)) and arginine (blue, R14 (KIIIA) and R18 (SIIIA)) residues. (B) Solution structure of analgesic μO-conotoxin MrVIB. Disulfide links are green. (C) Amino acid sequences of analgesic μ-conotoxins, KIIIA and SIIIA, and μO-conotoxins, MrVIA and MrVIB. * C-terminal amidation.

Figure 2

Effect of μO-conotoxin MrVIB on Na⁺ current amplitude of Na_v1.2, Na_v1.8 and their chimeras. (A) Schematic diagram of parent VGSC a-subunits rNa_v1.2 (open), hNa_v1.8 (filled) and chimeras 8822 and 8288. Roman numerals denote individual domains of the α-subunit, (B) Current–voltage relationship of rNa_v1.2, hNa_v1.8 and chimeras 8288 and 8822 in the absence (open symbols) and presence (closed symbols) of 1 μM MrVIB. Normalized peak currents (I/I₀) were plotted as a function of membrane potential. Insets: normalized depolarization-activated Na⁺ currents in Xenopus oocytes expressing rNa_v1.2, hNa_v1.8 and the chimeras. Oocytes were held at −80 mV and depolarized to potentials ranging from −80 to +40 mV in 10 mV increments (adapted from Knapp et al. [129]).