title: Antillatoxin is a sodium channel activator that displays unique efficacy in heterologously expressed rNav1.2, rNav1.4 and rNav1.5 α subunits.
abstract: BACKGROUND
  Antillatoxin (ATX) is a structurally unique lipopeptide produced by the marine cyanobacterium Lyngbya majuscula. ATX activates voltage-gated sodium channel α-subunits at an undefined recognition site and stimulates sodium influx in neurons. However, the pharmacological properties and selectivity of ATX on the sodium channel α-subunits were not fully characterized.
  
  
  RESULTS
  In this study, we characterized the pharmacological properties and selectivity of ATX in cells heterologously expressing rNa(v)1.2, rNa(v)1.4 or rNa(v)1.5 α-subunits by using the Na(+) selective fluorescent dye, sodium-binding benzofuran isophthalate. ATX produced sodium influx in cells expressing each sodium channel α-subunit, whereas two other sodium channel activators, veratridine and brevetoxin-2, were without effect. The ATX potency at rNa(v)1.2, rNa(v)1.4 and rNa(v)1.5 did not differ significantly. Similarly, there were no significant differences in the efficacy for ATX-induced sodium influx between rNa(v)1.2, rNa(v)1.4 and rNa(v)1.5 α-subunits. ATX also produced robust Ca²(+) influx relative to other sodium channel activators in the calcium-permeable DEAA mutant of rNa(v)1.4 α-subunit. Finally, we demonstrated that the 8-demethyl-8,9-dihydro-antillatoxin analog was less efficacious and less potent in stimulating sodium influx.
  
  
  CONCLUSIONS
  ATX displayed a unique efficacy with respect to stimulation of sodium influx in cells expressing rNa(v)1.2, rNa(v)1.4 and rNa(v)1.5 α-subunits. The efficacy of ATX was distinctive inasmuch as it was not shared by activators of neurotoxin sites 2 and 5 on VGSC α-subunits. Given the unique pharmacological properties of ATX interaction with sodium channel α-subunits, decoding the molecular determinants and mechanism of action of antillatoxin may provide further insight into sodium channel gating mechanisms.
authors.affiliation: Creighton University, School of Medicine, Department of Pharmacology, Omaha, NE 68178, USA.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Cao
authors.forename: William H
authors.initials: WH
authors.lastname: Gerwick
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Murray
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D055666:Lipopeptides / Q000494:pharmacology*; D008387:Marine Toxins / Q000494:pharmacology*; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D010456:Peptides, Cyclic / Q000494:pharmacology*; D021122:Protein Subunits / Q000096:biosynthesis / Q000502:physiology; D015222:Sodium Channels / Q000096:biosynthesis* / Q000235:genetics; D014701:Veratridine / Q000494:pharmacology
chemical_list: D001572:Benzofurans; D055666:Lipopeptides; D008387:Marine Toxins; D009124:Muscle Proteins; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D010456:Peptides, Cyclic; D021122:Protein Subunits; C568253:Scn2A protein, rat; C466180:Scn4a protein, rat; C568322:Scn5a protein, rat; D015222:Sodium Channels; C121886:antillatoxin; D014701:Veratridine; D002118:Calcium