title: Brevetoxin activation of voltage-gated sodium channels regulates Ca dynamics and ERK1/2 phosphorylation in murine neocortical neurons.
abstract: Voltage-gated sodium channels (VGSC) are involved in the generation of action potentials in neurons. Brevetoxins (PbTx) are potent allosteric enhancers of VGSC function and are associated with the periodic 'red tide' blooms. Using PbTx-2 as a probe, we have characterized the effects of activation of VGSC on Ca(2+) dynamics and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling in neocortical neurons. Neocortical neurons exhibit synchronized spontaneous Ca(2+) oscillations, which are mediated by glutamatergic signaling. PbTx-2 (100 nm) increased the amplitude and reduced the frequency of basal Ca(2+) oscillations. This modulatory effect on Ca(2+) oscillations produced a sustained rise in ERK1/2 activation. At 300 nm, PbTx-2 disrupted oscillatory activity leading to a sustained increase in intracellular Ca(2+) ([Ca(2+)](i)) and induced a biphasic, activation followed by dephosphorylation, regulation of ERK1/2. PbTx-2-induced ERK1/2 activation was Ca(2+) dependent and was mediated by Ca(2+) entry through manifold routes. PbTx-2 treatment also increased cAMP responsive element binding protein (CREB) phosphorylation and increased gene expression of brain-derived neurotrophic factor (BDNF). These findings indicate that brevetoxins, by influencing the activation of key signaling proteins, can alter physiologic events involved in survival in neocortical neurons, as well as forms of synaptic plasticity associated with development and learning.
authors.affiliation: University of Georgia, College of Veterinary Medicine, Department of Physiology and Pharmacology, Athens, Georgia, USA.
authors.forename: Shashank M
authors.initials: SM
authors.lastname: Dravid
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Baden
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Murray
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004798:Enzymes / Q000187:drug effects / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008387:Marine Toxins / Q000494:pharmacology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D035964:Oxocins / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D000095702:Polyether Toxins
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002118:Calcium; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D004798:Enzymes; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D008387:Marine Toxins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009498:Neurotoxins; D035964:Oxocins; D015222:Sodium Channels; C051732:Ptychodiscus brevis T2 toxin; C053342:brevetoxin; D000095702:Polyether Toxins