11,12 -Epoxyeicosatrienoic acid (11,12 EET) reduces excitability and excitatory transmission in the hippocampus

Abstract

Recent studies suggest a role for the arachidonic acid-derived epoxyeicosatrienoic acids (EETs) in attenuating epileptic seizures. However, their effect on neurotransmission has never been investigated in detail. Here, we studied how 11,12- and 14,15 EET affect excitability and excitatory neurotransmission in mouse hippocampus. 11,12 EET (2 μM), but not 14,15 EET (2 μM), induced the opening of a hyperpolarizing K conductance in CA1 pyramidal cells. This action could be blocked by BaCl, the G protein blocker GDPβ-S and the GIRK1/4 blocker tertiapin Q and the channel was thus identified as a GIRK channel. The 11,12 EET-mediated opening of this channel significantly reduced excitability of CA1 pyramidal cells, which could not be blocked by the functional antagonist EEZE (10 μM). Furthermore, both 11,12 EET and 14,15 EET reduced glutamate release on CA1 pyramidal cells with 14,15 EET being the less potent regioisomer. In CA1 pyramidal cells, 11,12 EET reduced the amplitude of excitatory postsynaptic currents (EPSCs) by 20% and the slope of field excitatory postsynaptic potentials (fEPSPs) by 50%, presumably via a presynaptic mechanism. EEZE increased both EPSC amplitude and fEPSP slope by 40%, also via a presynaptic mechanism, but failed to block 11,12 EET-mediated reduction of EPSCs and fEPSPs. This strongly suggests the existence of distinct targets for 11,12 EET and EEZE in neurons. In summary, 11,12 EET substantially reduced excitation in CA1 pyramidal cells by inhibiting the release of glutamate and opening a GIRK channel. These findings might explain the therapeutic potential of EETs in reducing epileptiform activity.

Soluble Epoxide Hydrolase Inhibitor and 14,15-Epoxyeicosatrienoic Acid-Facilitated Long-Term Potentiation through cAMP and CaMKII in the Hippocampus

“…Furthermore, the reduction of the plasma levels of prostaglandin E2 by sEHI did not influence the CYP450 in an LPS-treated rat [ 31 ]. Recently, studies pointed that CYP2J was distributed in cell bodies and 11, 12-EET reduced the neurotransmission in hippocampal CA1-CA3 area [ 32 ]. Thus, the sEHI and 14,15-EET increased the LTP and weather the effect the protein level or enzyme activity of CYP and sEH in hippocampus still needs further investigate.…”

Cytochrome P450 Metabolism of Polyunsaturated Fatty Acids and Neurodegeneration

“…It should be mentioned that in all these studies, non-neural cells were used as target cells, implying that this observation might not be applicable to neuronal cells, as the cell type used can be a key factor in determining the type of GPCR activation by EETs. Keeping these ideas in mind, Mule et al used CA1 pyramidal cells (PCs) in the mouse hippocampus and demonstrated that the 11,12 EET mediated opening of a G protein-coupled inwardly-rectifying potassium (GIRK) channel through the activation of Gi/o proteins, introducing a new EETs-dependent cellular pathway, which remains to be elucidated [ 286 ]. The activation of Gi/o proteins corroborate other studies suggesting that EETs are a potential target for the μ-opioid receptor, a GPCR system mainly linked to Gi/o proteins [ 287 , 288 ].…”

Oxidized Lipids in Persistent Pain States

“…In this reaction, one of the four double bonds of AA is oxidized to an epoxide. Depending on the site of oxygenation, this leads to the production of one of the four regioisomers: 5,6-EET, 8,9-EET, 11,12-EET or 14,15-EET (Marowsky et al, 2009; Sisignano et al, 2012; Mule et al, 2017). EETs can be released from cells to act as paracrine signaling mediators (Sisignano et al, 2012).…”

“…In the neuronal system, 11,12-EET opens G protein-coupled inward rectifier potassium (GIRK) channels in CA1 pyramidal cells in mouse hippocampus via G i/o proteins (Mule et al, 2017). This leads to reduced excitatory transmission in hippocampus acting on pre- and postsynaptic targets (Mule et al, 2017).…”

“…In the neuronal system, 11,12-EET opens G protein-coupled inward rectifier potassium (GIRK) channels in CA1 pyramidal cells in mouse hippocampus via G i/o proteins (Mule et al, 2017). This leads to reduced excitatory transmission in hippocampus acting on pre- and postsynaptic targets (Mule et al, 2017). However, in cultured DRG neurons, 11,12-EET had no effect on the intracellular calcium concentration, since it may inhibit L-type Ca 2+ -channels independent of intracellular cAMP levels or protein phosphorylation (Chen et al, 1999).…”