Role of epoxyeicosatrienoic acids as autocrine metabolites in glutamate-mediated K + signaling in perivascular astrocytes

Haruki Higashimori, Víctor M. Blanco, Vengopal Raju Tuniki, John R. Falck, Jessica A. Filosa

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Epoxyeicosatrienoic acids (EETs), synthesized and released by astrocytes in response to glutamate, are known to play a pivotal role in neurovascular coupling. In vascular smooth muscle cells (VSMC), EETs activate large-conductance, Ca 2+-activated K + (BK) channels resulting in hyperpolarization and vasodilation. However, the functional role and mechanism of action for glial-derived EETs are still to be determined. In this study, we evaluated the effect of the synthetic EET analog 11-nonyloxy-undec-8(Z)-enoic acid (NUD-GA) on outward K + currents mediated by calcium-activated K + channels. Addition of NUD-GA significantly increased intracellular Ca2 + and outward K + currents in perivascular astrocytes. NUD-GA-induced currents were significantly inhibited by BK channel blockers paxilline and tetraethylammonium (TEA) (23.4 ± 2.4%; P < 0.0005). Similarly, NUD-GA-induced currents were also significantly inhibited in the presence of the small-conductance Ca 2+-activated K + channel inhibitor apamin along with a combination of blockers against glutamate receptors (12.8 ± 2.70%; P < 0.05). No changes in outward currents were observed in the presence of the channel blocker for intermediate-conductance K + channels TRAM-34. Blockade of the endogenous production of EETs with N-methylsulfonyl-6-(2- propargyloxyphenyl-)hexanamide (MS-PPOH) significantly blunted (dl)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD)-induced outward K + currents (P < 0.05; n = 6). Both NUD-GA and t-ACPD significantly increased BK channel single open probability; the later was blocked following MS-PPOH incubation. Our data supports the idea that EETs are potent K + channel modulators in cortical perivascular astrocytes and further suggest that these metabolites may participate in NVC by modulating the levels of K + released at the gliovascular space.

Original languageEnglish (US)
Pages (from-to)C1068-C1078
JournalAmerican Journal of Physiology - Cell Physiology
Issue number5
StatePublished - Nov 2010


  • Calcium imaging
  • Calcium-activated potassium channels
  • Electrophysiology

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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