Voltage-Gated Sodium Channels: A Prominent Target of Marine Toxins

Abstract

Voltage-gated sodium channels (VGSCs) are considered to be one of the most important ion channels given their remarkable physiological role. VGSCs constitute a family of large transmembrane proteins that allow transmission, generation, and propagation of action potentials. This occurs by conducting Na+ ions through the membrane, supporting cell excitability and communication signals in various systems. As a result, a wide range of coordination and physiological functions, from locomotion to cognition, can be accomplished. Drugs that target and alter the molecular mechanism of VGSCs’ function have highly contributed to the discovery and perception of the function and the structure of this channel. Among those drugs are various marine toxins produced by harmful microorganisms or venomous animals. These toxins have played a key role in understanding the mode of action of VGSCs and in mapping their various allosteric binding sites. Furthermore, marine toxins appear to be an emerging source of therapeutic tools that can relieve pain or treat VGSC-related human channelopathies. Several studies documented the effect of marine toxins on VGSCs as well as their pharmaceutical applications, but none of them underlined the principal marine toxins and their effect on VGSCs. Therefore, this review aims to highlight the neurotoxins produced by marine animals such as pufferfish, shellfish, sea anemone, and cone snail that are active on VGSCs and discuss their pharmaceutical values.

Current Trends and New Challenges in Marine Phycotoxins

“…This study determined the amino acids directly binding to the neurotoxin. STX and TTX bind to VGSCs but with different range of affinities for each isoform [ 32 ]. Thus, the sodium channels alpha subunits (Na v ) Na v 1.1 (EC 50 6 nM), Na v 1.2 (EC 50 18 nM), Na v 1.3 (EC 50 4 nM), Na v 1.4 (EC 50 25 nM), Na v 1.6 (EC 50 6 nM), and Na v 1.7 (EC 50 24.5 nM), are highly TTX-sensitive, while Na v 1.5 (EC 50 5.7 µM), Na v 1.8 (EC 50 60 µM), and Na v 1.9 (EC 50 40 µM) are considered TTX-resistant [ 84 ].…”

“…In contrast to PSTs and TTXs, CTXs and BTXs maintain VGSCs in an active form [ 32 ]. CTXs and BTXs bind to site 5 of VGSCs, inducing an open state, subsequently allowing Na + passage inside cells.…”

“…CTXs and BTXs bind to site 5 of VGSCs, inducing an open state, subsequently allowing Na + passage inside cells. VGSC site 5 is comprised of the transmembrane segments S6 and S5 of the α-subunit domains I and IV, respectively [ 32 , 112 ]. CTXs bind to this site from the intracellular side of VGSCs ( Figure 2 ) [ 77 ].…”

“…When humans consume fish containing CTXs in sufficient amounts, the expected gastrointestinal, cardiovascular, and neurological symptoms of Ciguatera are classically presented within 1–6 h of fish ingestion [ 26 , 32 ]. The neurological symptoms include paresthesia, dysesthesia, vertigo, and sensory abnormalities such as metallic taste, pruritus, arthralgia, myalgia, dental pain, and cold allodynia, a pathognomonic Ciguatera symptom that is characterized by burning pain in response to a cold stimulus [ 128 ].…”

“…However, until now there has been no evidence of their involvement in human Ciguatera cases [ 30 ]. Ciguatoxins are chemically similar to brevetoxins ( Figure 1 J and K) and both act on voltage-gated sodium channels by binding to receptor site 5, causing depolarization of neuronal and muscle cell membranes and triggering human and animal neurological symptoms ( Figure 2 ) [ 31 , 32 ]. Brevetoxins (BTXs) are a group of polyether-toxins that cause neurotoxic shellfish poisoning (NSP) named after the more or less pronounced neurological symptoms that co-occur with gastrointestinal signs.…”