Antillatoxin-Stimulated Neurite Outgrowth Involves the Brain-Derived Neurotrophic Factor (BDNF) - Tropomyosin Related Kinase B (TrkB) Signaling Pathway.

Journal Article (Journal Article)

Voltage-gated sodium channel (VGSC) activators promote neurite outgrowth by augmenting intracellular Na+ concentration ([Na+ ]i ) and upregulating N-methyl-d-aspartate receptor (NMDAR) function. NMDAR activation stimulates calcium (Ca2+ ) influx and increases brain-derived neurotrophic factor (BDNF) release and activation of tropomyosin receptor kinase B (TrkB) signaling. The BDNF-TrkB pathway has been implicated in activity-dependent neuronal development. We have previously shown that antillatoxin (ATX), a novel lipopeptide isolated from the cyanobacterium Moorea producens , is a VGSC activator that produces an elevation of [Na+ ]i . Here we address the effect of ATX on the synthesis and release of BDNF and determine the signaling mechanisms by which ATX enhances neurite outgrowth in immature cerebrocortical neurons. ATX treatment produced a concentration-dependent release of BDNF. Acute treatment with ATX also resulted in increased synthesis of BDNF. ATX stimulation of neurite outgrowth was prevented by pretreatment with a TrkB inhibitor or transfection with a dominant-negative Trk-B. The ATX activation of TrkB and Akt was blocked by both a NMDAR antagonist (MK-801) and a VGSC blocker (tetrodotoxin). These results suggest that VGSC activators such as the structurally novel ATX may represent a new pharmacological strategy to promote neuronal plasticity through a NMDAR-BDNF-TrkB-dependent mechanism.

Full Text

Duke Authors

Cited Authors

  • Mehrotra, S; Pierce, ML; Cao, Z; Jabba, SV; Gerwick, WH; Murray, TF

Published Date

  • March 2022

Published In

Volume / Issue

  • 85 / 3

Start / End Page

  • 562 - 571

PubMed ID

  • 35239341

Pubmed Central ID

  • PMC9245549

Electronic International Standard Serial Number (EISSN)

  • 1520-6025

International Standard Serial Number (ISSN)

  • 0163-3864

Digital Object Identifier (DOI)

  • 10.1021/acs.jnatprod.1c01001

Language

  • eng