Abstract
Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (NaV), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on NaV1.1–1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective NaV toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes, an increase in the inactivation time constant was observed only at NaV1.8, while the slope factor of the conductance-voltage curves was significantly increased for NaV1.7 and peak current was significantly increased for NaV1.6. Accordingly, P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively. The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of NaV isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation.
Highlights
(P-CTX-1), on NaV1.1–1.9 using imaging and electrophysiological approaches
We found that Pacific ciguatoxin-1 (P-CTX-1)-induced Ca2+ responses were qualitatively similar in colonic sensory neurons to those in non-colonic neurons (Fig. 5c), with 83.3% (15/18) of colonic dorsal root ganglion (DRG) neurons activated by P-CTX-1
While it is established that these manifestations of ciguatoxin poisoning are likely attributable to activation of NaV isoforms expressed in sensory neurons, cardiac tissue and skeletal muscle, the effects of ciguatoxin on individual NaV isoforms and their relative contribution to the symptomatology of ciguatera has not been assessed systematically
Summary
(P-CTX-1), on NaV1.1–1.9 using imaging and electrophysiological approaches. P-CTX-1 is essentially a non-selective NaV toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes, an increase in the inactivation time constant was observed only at NaV1.8, while the slope factor of the conductance-voltage curves was significantly increased for NaV1.7 and peak current was significantly increased for NaV1.6. Ciguatera is the most common non-bacterial form of fish-borne illness and is caused by the consumption of fish contaminated with ciguatoxins[1] These polycyclic ethers are lipophilic, heat stable ichthyotoxins that originate from benthic dinoflagellates of the genus Gambierdiscus that bloom in tropical and sub-tropical oceans around the world. As bradycardia occur more rarely and often in more severe cases of poisoning[12,13,14,15] This diverse symptomatology is believed to be caused by the interaction of the ciguatoxins with site 5 of the voltage-gated sodium channels (NaV)[11,16,17,18]. Pacific ciguatoxin-1 (P-CTX-1), the most potent ciguatoxin congener thought to be responsible for the majority of symptoms associated with ciguatera in the Pacific[19], elicits varied effects on the electrophysiological properties of NaV channels and as a consequence enhances neuronal excitability. The aims of the present study were to determine the relative activity and subtype-selectivity of the most potent congener of the ciguatoxins, P-CTX-1, on the mammalian NaV isoforms NaV1.1–1.9 and to define the NaV isoforms that contribute to the in vivo symptomatology associated with ciguatera
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