Tài liệu Báo cáo khoa học: Marine toxins and the cytoskeleton: okadaic acid and dinophysistoxins

MINIREVIEW

Marine toxins and the cytoskeleton: okadaic acid

and dinophysistoxins

Carmen Vale and Luis M. Botana

Departamento de Farmacologı´a, Facultad de Veterinaria, USC, Lugo, Spain

Introduction

The syndrome diarrheic shellfish poisoning (DSP) was

first recognized in Japan 30 years ago. Although fatali￾ties associated with DSP-contaminated shellfish have

not been reported, this intoxication has become a seri￾ous problem for public health and for the economy of

aquaculture industries in several parts of the world.

Symptoms of DSP poisoning are mainly gastrointesti￾nal problems such as diarrhea, nausea, vomiting, and

abdominal pain. The major toxin involved in DSP is a

polyether derivative named dinophysistoxin-1 (DTX1).

Another previously identified polyether fatty acid com￾pound, named okadaic acid (OA), was found to be

one of the toxic components of DSP [1]. OA was first

isolated from the marine sponges Halichondria okadaii

and Halichondria melanodocia, and it was subsequently

shown to be produced by marine dinoflagellates of the

genera Dinophysis and Prorocentrum [2,3]. DTX1 was

confirmed to be 35S-methylokadaic acid [1]. The

molecular structures of OA and its analogs are shown

in Fig. 1.

Molecular and cellular effects of

diarrheic shellfish toxin exposure

The Ser/Thr protein phosphatases

Ser⁄Thr protein phosphatases represent a class of

enzymes in eukaryotic cells that catalyze the dephos￾Keywords

actin; cytoskeleton; diarrheic shellfish

poisoning; dinophysistoxins; DSP; methyl

okadaate; microtubules; OA; okadaic acid;

phycotoxin

Correspondence

C. Vale, Departamento de Farmacologı´a,

Facultad de Veterinaria, Campus

Universitario s/n 27002, USC, Lugo, Spain

Fax ⁄ Tel: +34 982 252 242

E-mail: [email protected]

(Received 4 July 2008, revised 15

September 2008, accepted 25

September 2008)

doi:10.1111/j.1742-4658.2008.06711.x

Okadaic acid (OA) and its analogs, the dinophysistoxins, are potent inhibi￾tors of protein phosphatases 1 and 2A. This action is well known to cause

diarrhea and gastrointestinal symptons when the toxins reach the digestive

tract by ingestion of mollusks. A less well-known effect of these group of

toxins is their effect in the cytoskeleton. OA has been shown to stimulate

cell motility, loss of stabilization of focal adhesions and a consequent loss

of cytoskeletal organization due to an alteration in the tyrosine-phosphory￾lated state of the focal adhesion kinases and paxillin. OA causes cell round￾ing and loss of barrier properties through mechanisms that probably

involve disruption of filamentous actin (F-actin) and ⁄ or hyperphosphoryla￾tion and activation of kinases that stimulate tight junction disassembly.

Neither methyl okadaate (a weak phosphatase inhibitor) nor OA modify

the total amount of F-actin, but both toxins cause similar changes in the

F-actin cytoskeleton, with strong retraction and rounding, and in many

cases cell detachment. OA and dinophysistoxin-1 (35S-methylokadaic acid)

cause rapid changes in the structural organization of intermediate fila￾ments, followed by a loss of microtubules, solubilization of intermediate

filament proteins, and disruption of desmosomes. The detailed pathways

that coordinate all these effects are not yet known.

Abbreviations

AD, Alzheimer’s disease; DSP, diarrheic shellfish poisoning; DTX1, dinophysistoxin-1; F-actin, filamentous actin; FAK, focal adhesion kinase;

IF, intermediate filament; OA, okadaic acid; TPA, 12-O-tetradecanoylphorbol-13-acetate.

6060 FEBS Journal 275 (2008) 6060–6066 ª 2008 The Authors Journal compilation ª 2008 FEBS