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

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 (Nay 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 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.