Antillatoxin, a novel lipopeptide, enhances neurite outgrowth in immature cerebrocortical neurons through activation of voltage-gated sodium channels

S. V. Jabba, A. Prakash, S. M. Dravid, W. H. Gerwick, Thomas F. Murray

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Antillatoxin (ATX) is a structurally novel lipopeptide that activates voltage-gated sodium channels (VGSC) leading to sodium influx in cerebellar granule neurons and cerebrocortical neurons 8 to 9 days in vitro (Li et al., 2001; Cao et al., 2008). However, the precise recognition site for ATX on the VGSC remains to be defined. Inasmuch as elevation of intracellular sodium ([Na+]i) may increase N-methyl-Daspartate receptor (NMDAR)-mediated Ca2+ influx, Na+ may function as a signaling molecule. We hypothesized that ATX may enhance neurite outgrowth in cerebrocortical neurons by elevating [Na+]i and augmenting NMDAR function. ATX (30-100 nM) robustly stimulated neurite outgrowth, and this enhancement was sensitive to the VGSC antagonist, tetrodotoxin. To unambiguously demonstrate the enhancement of NMDA receptor function by ATX, we recorded single-channel currents from cell-attached patches. ATX was found to increase the open probability of NMDA receptors. Na+-dependent up-regulation of NMDAR function has been shown to be regulated by Src family kinase (SFK) (Yu and Salter, 1998). The Src kinase inhibitor PP2 abrogated ATXenhanced neurite outgrowth, suggesting a SFK involvement in this response. ATX-enhanced neurite outgrowth was also inhibited by the NMDAR antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate (MK-801), and the calmodulin-dependent kinase kinase (CaMKK) inhibitor, 1,8-naphthoylene benzimidazole-3-carboxylic acid (STO-609), demonstrating the requirement for NMDAR activation with subsequent downstream engagement of the Ca2+-dependent CaMKK pathway. These results with the structurally and mechanistically novel natural product, ATX, confirm and generalize our earlier results with a neurotoxin site 5 ligand. These data suggest that VGSC activators may represent a novel pharmacological strategy to regulate neuronal plasticity through NMDAR-dependent mechanisms.

Original languageEnglish (US)
Pages (from-to)698-709
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume332
Issue number3
DOIs
StatePublished - Mar 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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