A study on mechanisms of toxic actions of ciguatoxins: existence of functional relationship between CTX3C and charged residues of voltage sensors in Nav1.4 sodium channel

Abstract

Ciguatoxins, a group of virulent marine toxins, are bound to ''site 5'' inside voltage-dependent sodium channels and alter their kinetics dramatically; this is probably responsible for clinical symptoms of ciguatoxin poisoning or ciguatera. Although ciguatoxins are known to affect the voltage dependency of both activation and inactivation kinetics, site 5 has not been functionally clarified. This study, therefore, targeted putative voltage sensors as a receptor for ciguatoxins. We constructed mutants, in which 1 of 23 basic residues was substituted with glutamine in the S4 segment for each of four domains. We then examined the effects of a synthetic ciguatoxin congener CTX3C on these mutants. Notably, the suppressive effect of CTX3C on the sodium current (I Na ) amplitude of domain 2 mutants, which carried a mutation in the basic S4 residue of domain 2, was either reduced or eliminated. Kinetic analyses of domain 2 mutants in comparison with those of the wild type and other mutants revealed that the negative shift of the steady-state inactivation curve (V 1/2inact D) was significantly decreased. The resistance of domain 2 mutants to CTX3C in terms of changes in V 1/2inact is suggested to be closely related to resistance to the suppressive effect of CTX3C on the I Na amplitude. This is the first report to demonstrate the existence of a functional relationship between a ciguatoxin congener and voltage sensor segments in domain 2 of the a-subunit of voltage-dependent sodium channels, although further studies are needed to locate a ciguatoxin receptor.

Voltage-sensor conformation shapes the intra-membrane drug binding site that determines gambierol affinity in Kv channels

“…The binding site for gambierol is reminiscent of the neurotoxin site 5 in Nav channels (Catterall et al, 2007;Trainer et al, 1991Trainer et al, , 1994. Interestingly, the affinity of the Nav1.4 channel for the ladder-shaped polyether toxin ciguatoxin-3C could be reduced by neutralizing a charged residue in the VSD of domain 2 (Yamaoka et al, 2011). This observation is in line with our data, suggesting that the mechanism of action of (some) polyether toxins on Nav and Kv channels is influenced by the VSD.…”

Brevetoxin, the Dinoflagellate Neurotoxin, Localizes to Thylakoid Membranes and Interacts with the Light‐Harvesting Complex II (LHCII) of Photosystem II

“…The molecular target of these toxins is typically a transmembrane protein or ion channel containing one or more α‐helices, to which PE ladders bind with extremely high affinities (nanomolar to picomolar K d values). The brevetoxins and ciguatoxin bind to and activate the voltage‐gated sodium channel (VGSC) 4. 21 To date, at least ten different sodium channel subtypes have been identified, with the brevetoxins and ciguatoxin specifically targeting the skeletal muscle and cardiac channel subtypes (Na v 1.4 and Na v 1.5, respectively).…”

“…In humans, the brevetoxins are the causative agents of a syndrome known as neurotoxic shellfish poisoning (NSP), as well as respiratory distress in beach visitors through exposure to aerosolized toxins 3. Ciguatoxin, maitotoxin (not shown), gambieric acid, and gambierol, produced by the dinoflagellate Gambierdiscus toxicus , are responsible for ciguatera fish poisoning (CSP),4 whereas yessotoxins from Protoceratium reticulatum have been associated with diarrheic shellfish poisoning (DSP) 5…”

The Mechanism of Action of Microalgal Toxins Interacting with NaV and KV Channels

“…More recently, chimeric constructs between Na V 1.8 and Na V 1.4 channels implicated DI and DII in the high affi nity of Nav1.8 for synthetic ciguatoxin P-CTX-3C (Yamaoka et al 2009). Subsequently, the same group suggested a functional relationship between this ciguatoxin and a charged residue in DII voltage sensor of Na V 1.4 (Yamaoka et al 2011). Hence, the receptor site 5 on Na V channels has not yet been fully characterized and further studies are required to elucidate the binding site and the molecular mechanism of ciguatoxins on Na V channels.…”