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Review
. 2013 Nov 28;11(12):4698-723.
doi: 10.3390/md11124698.

Shellfish toxins targeting voltage-gated sodium channels

Fan Zhang  1 , Xunxun Xu, Tingting Li, Zhonghua Liu
Affiliations
Review

Shellfish toxins targeting voltage-gated sodium channels

Fan Zhang et al. Mar Drugs. .

Abstract

Voltage-gated sodium channels (VGSCs) play a central role in the generation and propagation of action potentials in excitable neurons and other cells and are targeted by commonly used local anesthetics, antiarrhythmics, and anticonvulsants. They are also common targets of neurotoxins including shellfish toxins. Shellfish toxins are a variety of toxic secondary metabolites produced by prokaryotic cyanobacteria and eukaryotic dinoflagellates in both marine and fresh water systems, which can accumulate in marine animals via the food chain. Consumption of shellfish toxin-contaminated seafood may result in potentially fatal human shellfish poisoning. This article provides an overview of the structure, bioactivity, and pharmacology of shellfish toxins that act on VGSCs, along with a brief discussion on their pharmaceutical potential for pain management.

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Figures

Figure 1
Figure 1
Schematic diagram of molecular structure and pharmacology of VGSCs. VGSCs comprise a core protein α-subunit and one or more auxiliary β-subunits. The α-subunit consists of four homologous domains designated I–IV. Each domain is comprised of six transmembrane helical segments (S1–S6), which are represented by cylinders. The central pore is formed by the transmembrane segments S5 and S6, ion selectivity filter is formed by the segments SS1 and SS2 (re-entrant loops, the light green box), and the voltage-sensor is formed by the transmembrane segments S1 to S4. The positively charged S4 segment is principally responsible for sensing changes in membrane potential, modulating channels to open or close. The fast inactivation gate is formed by intracellular linker between transmembrane domains III and IV and contains an IFM (orange balls), which plugs the pore and prevents Na+ internal flow. Auxiliary β-subunits of VGSCs are illustrated in red cylinders. N-linked carbohydrate chains are presented by ψ. Different colored regions represent seven neurotoxin receptor sites. Figure adapted from King et al. (2008, 2012) and Catterall et al. (2007) [9,10,11].
Figure 2
Figure 2
Structures and species of STX, and its analogs, produced by marine dinoflagellates. Figure adapted from Wang (2008) [27,62].
Figure 3
Figure 3
Structures of brevetoxins from marine dinoflagellates [27,62].
Figure 4
Figure 4
Structures of antillatoxin A, antillatoxin B and kalkitoxin [85,89,90].
Figure 5
Figure 5
Structures of Jamaicamide A–C [104].
Figure 6
Figure 6
Structures of crossbyanol A–D [107].
Figure 7
Figure 7
Structures of hoiamide A–D [108,109,110].
Figure 8
Figure 8
Structures of palmyrolide A [112].
Figure 9
Figure 9
Structures of palmyramide A [117].
See this image and copyright information in PMC

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