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 language | English (US) |
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Pages (from-to) | 203-215 |
Number of pages | 13 |
Journal | Biochemical Journal |
Volume | 438 |
Issue number | 1 |
DOIs | |
State | Published - Aug 15 2011 |
Externally published | Yes |
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