Marine toxins and the cytoskeleton

Abstract

One of the most striking features of marine toxins is that many of them produce diarrhea. This effect has been attributed to an effect on the cytoskeleton, with the consequent disorganization of the adherent cells on the intestinal cell barrier leading to an excess of liquid. But this has never been fully proven, as many neurotoxins show diarrheic effects that could be explained by an effect on the innervation system rather than on the epithelial intestinal cells. There is a wide diversity of mechanisms of action for marine toxins: phosphatase inhibition (okadaic acid), phosphodiesterase activation (yessotoxin), Na ⁄K-ATPase inhibition (palytoxin), Na channel blockage (saxitoxin, ciguatoxin, brevetoxin, conotoxin), nicotinic receptor antagonism (gymnodimin), mitogen-activated protein kinase activation (azaspiracid), Ca channel opening (maitotoxin), and K blockade (gambierol, conotoxin). Despite this complex array of modes of action, only pectenotoxins are known to target specifically the actin filaments. But regardless of the mechanism of action, most of the toxin groups have profound effects on cytoskeletal dynamics. The relevance of this is difficult to clarify, as the cytoskeleton is a common transduction step for many signals, but the effect of phycotoxins on the cytoskeleton is becoming a useful tool with which to investigate the toxicity and the mechanism of action of the toxins. This minireview series is intended to bring together a comprehensive set of data on four of the best recently studied toxin groups. Okadaic acid and their analogs, the dinophysistoxins, have been known for years as phosphatase inhibitors. They are very common worldwide, and important both economically, as a major cause of loss for shellfish producers, and scientifically, as okadaic acid is often used in research as a phosphatase inhibitor. Okadaic acid has been considered to be a very selective drug, in a similar fashion as initially thought for phorbol esters and protein kinase C, and its mode of action has clear implications for the dynamics of actin reorganization, but recent evidence indicates that phosphatases may not be the only targets of these toxins. The diarrhea caused by okadaic acid and analogs is so important that in the marine toxins field, members of the group are called diarrheic shellfish poisons. Palytoxin is well known to modify the function of the Na ⁄K-ATPase, but does not compete with ouabain, and its specific binding site has not yet been identified. The complexities of this compound and its many analogs make the group unique [largest nonrepetitive (peptide or sugar) molecule in nature], and also very interesting from a food safety perspective, as this group of compounds has been recently identified in Europe as a new risk phenomenom. Azaspiracids are currently by far the most complex toxin group and, 10 years after the first document reporting their presence, the mechanism of action remains elusive. Their complex transduction pathway is tightly linked to the cytoskeleton, and deserves a review. Finally, pectenotoxins are clearly associated with actin. Their action has been reported to involve a 1 : 1 binding with actin. However, the affinity of this binding is undefined as yet, and there are many unresolved questions regarding the implications of this effect for cell structure. Of all the marine toxin groups, okadaic acid, palytoxin, azaspiracids and pectenotoxins seem to be the most intriguing and interesting with regard to their effects on the cystoskeleton, and the four minireviews in this series describe what is known to date.