µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic Potential

Abstract

The Conus genus includes around 500 species of marine mollusks with a peculiar production of venomous peptides known as conotoxins (CTX). Each species is able to produce up to 200 different biological active peptides. Common structure of CTX is the low number of amino acids stabilized by disulfide bridges and post-translational modifications that give rise to different isoforms. µ and µO-CTX are two isoforms that specifically target voltage-gated sodium channels. These, by inducing the entrance of sodium ions in the cell, modulate the neuronal excitability by depolarizing plasma membrane and propagating the action potential. Hyperexcitability and mutations of sodium channels are responsible for perception and transmission of inflammatory and neuropathic pain states. In this review, we describe the current knowledge of µ-CTX interacting with the different sodium channels subtypes, the mechanism of action and their potential therapeutic use as analgesic compounds in the clinical management of pain conditions.

Keywords: conotoxin; ion current; pain transmission; sodium channel; µ-conotoxin.

Figure 1

Representative image of the voltage-gated sodium channel (Nav) state. At the resting potential, the channel is closed. In response to a voltage change impulse greater than the threshold potential of −55 mV, the channel is activated and Na⁺ ions enter into the cytosol down their concentration gradient, giving rise to the action potential. It is a sudden, transient depolarization of the membrane potential that reaches a peak and, then, is followed by repolarization.

Figure 2

(A) Schematic representation of the sodium channel structure comprising a core α subunit and two auxiliary β subunits. The alpha subunit contains four homologue domains (Domain I-Domain IV), each consisting of six transmembrane helices (S1–S6) reported as cylinders. The pore of the channel is formed by S5 and S6 helices in DI, while the voltage sensor is formed by S1–S4 helices in DI. Auxiliary β subunits of the channels as immunoglobulin-like folds are illustrated. µ-CTX binding site is located between S5 and S6 helices in DII. (B) Schematic representation of the top view of the extracellular face of the α-subunit Nav channel. The location of the µ-CTX binding site and the close local anesthetic binding site are indicated.

Figure 3

(A) Representative image of a cone snail predator showing internal venomous apparatus. The harpoon is the structure responsible for launching toxin and inducing paralysis of the prey. Chemical (B) and tridimensional (C) structure of µ-CTX-GIIIB, among the first toxin to be isolated from the venom of Conus geographus; B from https://pubchem.ncbi.nlm.nih.gov/compound/90469965#section=Top and (C) different colors indicate different residues.

Figure 4

(A) The µ-CTX isolated from different species of the genus Conus, Nav channels targeted, their distributions in different tissues, and their biological effects, which are proved or extrapolated from channel activity data. CNS is central nervous system; PNS is peripheral nervous system. (B) The µO-CTX isolated from different species of the genus Conus, Nav channels targeted, their distributions in different tissues, and their biological effects, which are proved or extrapolated from channel activity data.