title: Domoic acid-induced neurodegeneration resulting in memory loss is mediated by Ca2+ overload and inhibition of Ca2+ + calmodulin-stimulated adenylate cyclase in rat brain (review).
abstract: Domoic acid is a shellfish toxin which produces neurodegeneration and CNS dysfunction, notably a loss of short-term memory. This toxin was found in blue mussels (Mytilus edulis) cultivated in river water in the east coast of Prince Edward Island in Canada and caused human poisoning. The toxin was localized in the stomach of blue mussels, which was engorged with algae, Nitzschia pungens, that were filtered from the surrounding water. The toxin was isolated from contaminated mussels or phytoplankton, and identified chemically as domoic acid (DOM) which is a tricarboxylic amino acid. Due to its structural resemblance to glutamic, aspartic and kainic acids, DOM was considered to produce excitotoxicity by similar mechanism(s). However, the latest evidence indicates differences in its mode of action from these excitatory agonists. We propose that DOM induces toxicity via changes in intracellular concentration of Ca2+ ([Ca2+]i). Results of our studies demonstrate that DOM elevated [Ca2+]i in brain slices. Glucose deprivation and removal of Na+ from the Krebs-bicarbonate medium further elevated [Ca2+]i, suggesting a relationship between glucose metabolism (cell energy), Na+ and Ca2+ transfer across neuronal membrane. DOM-induced rise in [Ca2+]i was due to enhanced Ca2+ influx and its mobilization from the endoplasmic reticulum. In addition, diminished Ca2+-ATPase activity due to lack of ATP, and variable amounts and expression of calcium binding proteins (CaBP) appear to contribute to an elevation in [Ca2+]i in response to DOM. Most interestingly, DOM inhibited Ca2+ and calmodulin-stimulated adenylate cyclase activity in brain membranes, resulting in reduced level of cyclic AMP. Cyclic AMP is known to activate protein kinase A to enhance phosphorylation of Ca2+ channels, thereby, reducing Ca2+ influx to prevent the development of Ca2+ overload which is detrimental to neuronal cell function (neuroprotection). However, DOM reduced cyclic AMP level, diminishing the feedback control of cyclic AMP on Ca2+ influx via Ca2+ channels, thereby, allowing continuing enhanced Ca2+ influx, resulting in Ca2+ overload which adversely affects many intracellular processes to induce toxicity. Ca2+ and CaM-stimulated adenylate cyclase activity in brain is highly correlated with the acquisition and retention of memory in different organisms. Calcium binding proteins bind Ca2+ reversibly and provide intracellular Ca2+ buffering, thereby, protecting neuronal cell from damage by Ca2+ overload in response to DOM. DOM appears to interfere with the cross talk between Ca2+ and cyclic AMP which is necessary for neuronal cell function. We have also demonstrated that DOM stimulates GLU release from synaptosomes and may produce some of its toxic effects via excess GLU in the neuronal synapse. In conclusion, DOM-induced neurodegeneration resulting in a loss of memory is mediated by Ca2+ overload, inhibition of Ca2+ and CaM-stimulated adenylate cyclase activity, and/or by the enhanced GLU release in rat brain.
authors.affiliation: Department of Anatomy and Physiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown C1A 4P3, PEI, Canada. nijjar@upei.ca
authors.forename: M S
authors.initials: MS
authors.lastname: Nijjar
authors.forename: S S
authors.initials: SS
authors.lastname: Nijjar
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002147:Calmodulin / Q000494:pharmacology; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000633:toxicity*; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D051381:Rats
chemical_list: D002147:Calmodulin; D009498:Neurotoxins; D000262:Adenylyl Cyclases; D007608:Kainic Acid; D002118:Calcium