Antillatoxin (ATX) is a lipopeptide produced by the marine cyanobacterium Lyngbya majuscula. Atx, a Na+ channel activator, produces N-methyl-D-aspartate (NMDA) receptor mediated neurotoxicity in rat cerebellar granule neurons (CGNs). To determine whether ATX produced this neurotoxicity through an indirect mechanism, the influence of ATX on Glutamate release was ascertained. ATX produced a concentration-dependent increase in extracellular glutamate. This response was prevented by the Na+ channel antagonist tetrodotoxin (TTX). ATX caused a strong membrane depolarization with a magnitude comparable to that of 100 MM KCL. ATX also produced a concentration-dependent cytotoxicity as measured by lactate dehydrogenase activity. Ca+2 influx was measured using a fluorescent imaging plate reader (FLIPR). ATX produced concentration-dependent Ca+2 influx. The neurotoxic mechanisms of ATX are therefore similar to those of brevetoxins, which produce neuronal injury through depolarization-induced Na+! load, glutamate release, relief of Mg+2 block of NMDA receptors, and Ca+2 influx.