Type B brevetoxins show tissue selectivity for voltage-gated sodium channels: comparison of brain, skeletal muscle and cardiac sodium channels.
Brevetoxins and ciguatoxins are two classes of phycotoxins which exert their toxic effect by binding to site-5 of voltage-gated sodium channels. Sodium channels, a family of at least 10 structurally different proteins, are responsible for the rising phase of the action potential in membranes of neuronal, cardiac and muscular excitable cells. This work is a comparative study of the binding properties and the cytotoxic effects of ciguatoxins and brevetoxins on human embryonic cells (HEK) stably expressing either the skeletal muscle (Na(v)1.4), or the cardiac (Na(v)1.5) sodium channel alpha-subunit isoforms. We report that type A (PbTx-1) and type B (PbTx-3 and PbTx-2) brevetoxins as well as ciguatoxins target both cardiac and muscle channels; type B brevetoxins show isoform selectivity, presenting a lower affinity for the heart than the skeletal muscle channel. The lower selectivity of type B brevetoxins for heart sodium channels may result from a more rigid backbone structure than is found in type A brevetoxins and ciguatoxins.
Bottein Dechraoui
Marie-Yasmine
MY
Marine Biotoxins Program, Center for Coastal Environmental Health and Biomolecular Research, NOAA-National Ocean Service, 219 Fort Johnson Road, Charleston, SC 29412, USA.
Ramsdell
John S
JS
D000818:Animals; D001921:Brain / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002922:Ciguatoxins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D004141:Dinoflagellida; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects; D008387:Marine Toxins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009498:Neurotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009928:Organ Specificity; D035964:Oxocins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D020033:Protein Isoforms; D015222:Sodium Channels / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000095702:Polyether Toxins
D002922:Ciguatoxins; D008387:Marine Toxins; D009498:Neurotoxins; D035964:Oxocins; D020033:Protein Isoforms; D015222:Sodium Channels; C043466:brevetoxin B; D000095702:Polyether Toxins