PT  - JOURNAL ARTICLE
AU  - S. V. Jabba
AU  - A. Prakash
AU  - S. M. Dravid
AU  - W. H. Gerwick
AU  - T. F. Murray
TI  - Antillatoxin, a Novel Lipopeptide, Enhances Neurite Outgrowth in Immature Cerebrocortical Neurons through Activation of Voltage-Gated Sodium Channels
AID  - 10.1124/jpet.109.161802
DP  - 2010 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 698--709
VI  - 332
IP  - 3
4099  - http://jpet.aspetjournals.org/content/332/3/698.short
4100  - http://jpet.aspetjournals.org/content/332/3/698.full
SO  - J Pharmacol Exp Ther2010 Mar 01; 332
AB  - 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-d-aspartate 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 ATX-enhanced 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.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics