Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons

Abstract

The present study investigated the actions of the polyether marine toxin Pacific ciguatoxin-1 (P-CTX-1) on neuronal excitability in rat dorsal root ganglion (DRG) neurons using patch-clamp recording techniques. Under current-clamp conditions, bath application of 2-20 nM P-CTX-1 caused a rapid, concentration-dependent depolarization of the resting membrane potential in neurons expressing tetrodotoxin (TTX)-sensitive voltage-gated sodium (Nav) channels. This action was completely suppressed by the addition of 200 nM TTX to the external solution, indicating that this effect was mediated through TTX-sensitive Nav channels. In addition, P-CTX-1 also prolonged action potential and afterhyperpolarization (AHP) duration. In a subpopulation of neurons, P-CTX-1 also produced tonic action potential firing, an effect that was not accompanied by significant oscillation of the resting membrane potential. Conversely, in neurons expressing TTX-resistant Nav currents, P-CTX-1 failed to alter any parameter of neuronal excitability examined in this study. Under voltage-clamp conditions in rat DRG neurons, P-CTX-1 inhibited both delayed-rectifier and 'A-type' potassium currents in a dose-dependent manner, actions that occurred in the absence of alterations to the voltage dependence of activation. These actions appear to underlie the prolongation of the action potential and AHP, and contribute to repetitive firing. These data indicate that a block of potassium channels contributes to the increase in neuronal excitability, associated with a modulation of Nav channel gating, observed clinically in response to ciguatera poisoning.

A polyether biotoxin binding site on the lipid-exposed face of the pore domain of Kv channels revealed by the marine toxin gambierol

“…These larger toxins generally do not affect Kv channels (1, 2); if they bind, they are probably too large to fit properly or do not present the required functional group(s) to interact with the (cytoplasmic) gating machinery. Nevertheless, there is a study that reported inhibition of Kv currents in rat dorsal root ganglia neurons by the pacific CTX-1 with an IC 50 around 20 nM (30).…”

Gambierol Acts as a Functional Antagonist of Neurotoxin Site 5 on Voltage-Gated Sodium Channels in Cerebellar Granule Neurons

“…A more recent study using mouse taste cells has demonstrated that ciguatoxin (CTX3C) differs from gambierol in that it did not affect voltage-gated K ϩ channels (Ghiaroni et al, 2006). However, these results indicate that the actions of polyether toxins may differ as a function of cellular context inasmuch as ciguatoxin has been shown to inhibit K ϩ currents in dorsal root ganglion neurons (Birinyi-Strachan et al, 2005).…”

The modulation of voltage-gated potassium channels by anisotonicity in trigeminal ganglion neurons

“…Studies show that the inhibition of I K can depolarize the cell membrane, prolong AP duration, reduce the amplitude of afterhyperpolarization and lower the threshold for AP firing (Birinyi-Strachan et al, 2005;Safronov et al, 1996), while the inhibition of I A can induce repetitive firing (Amir et al, 2002;Storm, 1988). It is widely accepted that a decrease of VGPCs, including I K and I A , can increase the excitability of cells (Birinyi-Strachan et al, 2005;Yost, 1999).…”

“…Studies show that the inhibition of I K can depolarize the cell membrane, prolong AP duration, reduce the amplitude of afterhyperpolarization and lower the threshold for AP firing (Birinyi-Strachan et al, 2005;Safronov et al, 1996), while the inhibition of I A can induce repetitive firing (Amir et al, 2002;Storm, 1988). It is widely accepted that a decrease of VGPCs, including I K and I A , can increase the excitability of cells (Birinyi-Strachan et al, 2005;Yost, 1999). Recent evidences suggest that VGPCs participate in nociceptive signal transduction induced by inflammatory mediators (Harriott et al, 2006;Sculptoreanu et al, 2004;Stewart et al, 2003;Takeda et al, 2006;Yoshimura and de Groat, 1999;Xu et al, 2006) and nerve injury (Everill and Kocsis, 1999;Ishikawa et al, 1999;Rasband et al, 2001) in primary sensory neurons.…”