Arachidonic acid modulates Na + currents by non-metabolic and metabolic pathways in rat cerebellar granule cells

Yan Jia Fang, Meng Hua Zhou, Xiao Fei Gao, Hua Gu, Yan Ai Mei

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

AA (arachidonic acid), which possesses both neurotoxic and neurotrophic activities, has been implicated as a messenger in both physiological and pathophysiological processes. In the present study, we investigated the effects of both extracellular and intracellular application of AA on the activity of Na V (voltage-gated Na + channels) in rat cerebellar GCs (granule cells). The extracellular application of AA inhibited the resultant I Na (Na V current), wherein the current-voltage curve shifted to a negative voltage direction. Because this effect could be reproduced by treating the GCs with ETYA (eicosa-5,8,11,14-tetraynoic acid) or a membrane-impermeable analogue of AA, AA-CoA (arachidonoyl coenzyme A), we inferred that AA itself exerted the observed modulatory effects on I Na. In contrast, intracellular AA significantly augmented the elicited I Na peak when the same protocol that was used for extracellular AA was followed. The observed I Na increase that was induced by intracellular AA was mimicked by the AA cyclo-oxygenase metabolite PGE 2 (prostaglandin E 2), but not by ETYA. Furthermore, cyclooxygenase inhibitors decreased I Na and quenched AA-induced channel activation, indicating that the effect of intracellular AA on Na V was possibly mediated through AA metabolites. In addition, the PGE 2-induced activation of I Na was mimicked by cAMP and quenched by a PKA (protein kinase A) inhibitor, a G s inhibitor and EP (E-series of prostaglandin) receptor antagonists. The results of the present study suggest that extracellular AA modulates Na V channel activity in rat cerebellar GCs without metabolic conversion, whereas intracellular AA augments the I Na by PGE 2-mediated activation of cAMP/PKA pathways. These observations may explain the dual character of AA in neuronal pathogenesis.

Original languageEnglish (US)
Pages (from-to)203-215
Number of pages13
JournalBiochemical Journal
Volume438
Issue number1
DOIs
StatePublished - Aug 15 2011
Externally publishedYes

Keywords

  • Arachidonic acid
  • Cerebellar granule cell
  • Eicosa-5,8,11,14-tetraynoic acid (ETYA)
  • Prostaglandin E (PGE )
  • Voltage-gated Na channel current (I )
  • cAMP/protein kinase A (PKA)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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