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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.
Highlights
Cone snails are carnivorous and venomous molluscs belonging to the Conus genus (Figure S1)living mainly in the tropical marine areas
About 700 species of Cone snails express hundreds of peptide toxins collectively known as conotoxins (CTX) aimed to self-defense, competition and predation of other marine species by means of sting–structures that were reported to be fatal for human since from 300 years ago
Following studies on mice demonstrated that μ-KIIIA blocked almost 80% of the TTX-sensitive, but only 20% of the TTX-resistant Nav channels. These studies based on the expression of Nav channels in Xenopus oocytes evidenced a potent analgesic activity in mouse pain model after systemic administration, showing for the first time that μ-CTX can block neuronal subtypes of mammalian Nav channels [49]
Summary
Cone snails are carnivorous and venomous molluscs belonging to the Conus genus (Figure S1). Nav channels lasted for a few milliseconds and was quickly inactivated, giving rise to a cascade of other ion currents activation aimed to restore the original potential. Nav channel activators have been isolated from the venom of several animals, plants and bacteria, providing key insight into the pathophysiological roles of these channels [12] These studies established that drugs with anesthetic activity act on Na+ channels binding to a receptor located in the pore of the channel, through different mechanisms. The channels are closed whereas, after depolarization of the RP, the segment S4 is alerted giving rise to a brief opening of the pore and Na+ passage (the open state) to quickly shift to an inactivated state These main states are the basis for the sensitivity to drugs and inhibitors, which show different affinity for a specific state [14].
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