Inhibition of Voltage-Gated Potassium Currents by Gambierol in Mouse Taste Cells

Abstract

Ciguatera is a food poisoning caused by toxins of Gambierdiscus toxicus, a marine dinoflagellate. The neurological features of this intoxication include sensory abnormalities, such as paraesthesia, heightened nociperception, and also taste alterations. Here, we have evaluated the effect of gambierol, one of the possible ciguatera toxins, on the voltage-gated ion currents in taste cells. Taste cells are excitable cells endowed with voltage-gated Na+, K+, and Cl- currents (I(Na), I(K), and I(Cl), respectively). By applying the patch-clamp technique to single cells in isolated taste buds obtained from the mouse vallate papilla, we have recorded such currents and determined the effect of bath-applied gambierol. We found that this toxin markedly inhibited I(K) in the nanomolar range (IC50 of 1.8 nM), whereas it showed no significant effect on I(Na) or I(Cl) even at high concentration (1 microM). The block of I(K) was irreversible even after a 50-min wash. In addition to affecting the current amplitude, we found that gambierol significantly altered both the activation and inactivation processes of I(K). In conclusion, unlike other toxins involved in ciguatera, such as ciguatoxins, which affect the functioning of voltage-gated sodium channels, the preferred molecular target of gambierol is the voltage-gated potassium channel, at least in taste cells. Voltage-gated potassium currents play an important role in the generation of the firing pattern during chemotransduction. Thus, gambierol may alter action potential discharge in taste cells and this could be associated with the taste alterations reported in the clinical literature.

Gambierol, a toxin produced by the dinoflagellate Gambierdiscus toxicus, is a potent blocker of voltage-gated potassium channels

“…Compounds such as gambierol are described to be produced by G. toxicus dinoflagellates, but relatively little is known about their targets. Although sodium and potassium channels have been proposed in the literature as possible targets (Inoue et al, 2003;Ghiaroni et al, 2005;Louzao et al, 2006), very few papers can couple these targets to the intoxication symptoms (Cameron, 1993). In this article, we define VGPCs as a physiological target of gambierol, examine its selectivity and speculate on gambierol's role in CFS intoxications.…”

“…Since K v 1.2 is an important player in multiple sclerosis, gambierol might be considered as a lead compound in further study of the use of toxins in the treatment of pathogenic conditions. It has been suggested that the highly lipophilic gambierol molecules are expected to enter the lipid bilayer of the cell membranes and disrupt the normal lipid environment that surrounds the potassium channels and which would likely have effect on the channel operation (Ghiaroni et al, 2005). However, from our experiment where we tested the IV relationship in HK solution, we can conclude that at least the ion selectivity is not changed by gambierol since the reversal potential in control (−2.6 mV±2.3; n = 5) and with 35 nM gambierol (−5.7 mV±2.8; n = 3) is statistically not significantly different (P>0.05; n = 3) and in the range of the calculated reversal potential (…”

Developmental Biology of Neoplastic Growth

“…toxicus produces a variety of polyethers with potent biological activities, among which gambierol (19) is intriguing because it strongly inhibits voltage-gated K + channels with an IC 50 value of 1.8 ng/ml and is toxic to mice with LD 50 50 μg/kg (Ghiaroni et al 2005). Gambierol's mechanism of action is discussed in Chap.…”

“…Gambierol has been reported to irreversibly inhibit K + currents in the nanomolar range in excitable taste cells (Ghiaroni et al 2005), with a maximum efficiency of 60%. In addition to affecting the K + current amplitude, gambierol significantly altered both activation and inactivation processes of K + currents, whereas it showed no significant effect on Na + or Cl − currents even at micromolar concentrations.…”

Recent Applications of the Suzuki-Miyaura Cross-coupling to Complex Polycyclic Ether Synthesis

“…3 5 Very recently, it has been reported that gambierol acts as a potent and subtype selective inhibitor of voltage gated potassium channels. 6,7 As is often the case for many marine natural products, due to their scarce natural abundance and the dif culties of chemical modi cation, the biological characteristics of many of these polycyclic ether molecules have not yet been fully investigated. An increasingly important and often sole solution to these supply problems is chemical total synthesis.…”