Conotoxins Targeting Neuronal Voltage-Gated Sodium Channel Subtypes: Potential Analgesics?

Oliver Knapp,David J Adams,Jeffrey R Mcarthur

doi:10.3390/toxins4111236

Oliver Knapp, David J Adams + Show 1 more

Open Access

https://doi.org/10.3390/toxins4111236

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Journal: Toxins	Publication Date: Nov 8, 2012
Citations: 174	License type: CC BY 3.0

Affiliation: RMIT University

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.

Highlights

Depolarization-activated sodium (Na+)-selective ion channels are large transmembrane proteins present in central and peripheral neurons, and skeletal, cardiac and smooth muscle
Voltage-gated sodium channels (VGSC) consist of a 260 kD pore-forming α-subunit, of which there are nine identified mammalian subtypes (Nav1.1–Nav1.9)
Nav1.3 is usually expressed in embryogenesis than adulthood [32], but expression levels increase in peripheral dorsal root ganglion (DRG) neurons after nerve injury and inflammation [33]

Summary

Introduction

Depolarization-activated sodium (Na+)-selective ion channels ( known as voltage-gated sodium channels, VGSCs) are large transmembrane proteins present in central and peripheral neurons, and skeletal, cardiac and smooth muscle. In response to a small depolarization of the membrane potential, VGSCs cause a large depolarization by facilitating Na+ entry into the cell. VGSCs consist of a 260 kD pore-forming α-subunit, of which there are nine identified mammalian subtypes (Nav1.1–Nav1.9). S4 transmembrane segment moves in response to voltage and couples this movement to opening and closing of the pore domain. The fatty acyl chains extend into the central cavity, perhaps allowing small, hydrophobic channel modulators reach their binding site [2]. Β-subunits comprise a single transmembrane segment, short intracellular C-terminus and large extracellular N-terminal domain harbouring two β-sheets in an immunoglobulin-like fold. Two studies suggest the intracellular domains of VGSC α- and β-subunits interact, and that this interaction may be important for modulating certain VGSC subtypes [11,12]

VGSC Subtypes Involved in Pain

Conotoxins

Multiple Sites of μ- and μO-Conotoxin Action

Conotoxins—Analgesics of the Future?

Conflict of Interest