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TOXICOLOGY

Influence of Lipid-Soluble Gating Modifier Toxins on Sodium Influx in Neocortical Neurons

Creighton University, School of Medicine, Department of Pharmacology, Omaha, Nebraska (Z.C., J.G., T.F.M.); Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California (W.H.G.); University of North Carolina, Center for Marine Science Research, Wilmington, North Carolina (D.G.B.); and Department of Chemistry, University of Utah, Salt Lake City, Utah (J.D.R.)

The electrical signals of neurons are fundamentally dependent on voltage-gated sodium channels (VGSCs), which are responsible for the rising phase of the action potential. An array of naturally occurring and synthetic neurotoxins have been identified that modify the gating properties of VGSCs. Using murine neocortical neurons in primary culture, we have compared the ability of VGSC gating modifiers to evoke Na⁺ influx. Intracellular sodium concentration ([Na⁺]_i) was monitored using the Na⁺-sensitive fluorescent dye, sodium-binding benzofuran isophthalate. All sodium channel gating modifier compounds tested produced a rapid and concentration-dependent elevation in neuronal [Na⁺]_i. The increment in [Na⁺]_i exceeded 40 mM at high concentrations of brevetoxins, batrachotoxin, and the novel lipopeptide, antillatoxin. The maximal increments in neuronal [Na⁺]_i produced by neurotoxin site 2 alkaloids, veratridine and aconitine, and the pyrethroid deltamethrin were somewhat lower with maximal [Na⁺]_i increments of less than 40 mM. The rank order of efficacy of sodium channel gating modifiers was brevetoxin (PbTx)-1 > PbTx-desoxydioxolane > batrachotoxin > antillatoxin > PbTx-2 = PbTx-3 > PbTx-3-naphthoate > veratridine > deltamethrin > aconitine > gambierol. These data demonstrate that the ability of sodium channel gating modifiers to act as partial agonists is shared by compounds acting at both neurotoxin sites 2 and 5. The concentration-dependent increases in [Na⁺]_i produced by PbTx-2, antillatoxin, veratridine, deltamethrin, aconitine, and gambierol were all abrogated by tetrodotoxin, indicating that VGSCs represent the sole pathway of Na⁺ entry after exposure to gating modifier neurotoxins.

Address correspondence to: Dr. Thomas F. Murray, Creighton University School of Medicine, Department of Pharmacology, Omaha, NE 68178. E-mail: tfmurray{at}creighton.edu

This article has been cited by other articles:

				J. George, S. M. Dravid, A. Prakash, J. Xie, J. Peterson, S. V. Jabba, D. G. Baden, and T. F. Murray Sodium Channel Activation Augments NMDA Receptor Function and Promotes Neurite Outgrowth in Immature Cerebrocortical Neurons J. Neurosci., March 11, 2009; 29(10): 3288 - 3301. [Abstract] [Full Text] [PDF]