12-hydroxyeicosatetrenoate (12-HETE) attenuates AMPA receptor-mediated neurotoxicity: evidence for a G-protein-coupled HETE receptor.

Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. ahampson@cortexpharm.com

The Journal of neuroscience : the official journal of the Society for Neuroscience 2002 Jan 1

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12-hydroxyeicosatetraenoic acid (12-HETE) is a neuromodulator that is synthesized during ischemia. Its neuronal effects include attenuation of calcium influx and glutamate release as well as inhibition of AMPA receptor (AMPA-R) activation. Because 12-HETE reduces ischemic injury in the heart, we examined whether it can also reduce neuronal excitotoxicity. When treated with 12-(S)HETE, cortical neuron cultures subjected to AMPA-R-mediated glutamate toxicity suffered up to 40% less damage than untreated cultures. The protective effect of 12-(S)HETE was concentration-dependent (EC50 = 88 nm) and stereostructurally selective. Maximal protection was conferred by 300 nm 12-(S)HETE; 300 nm 15-(S)HETE was similarly protective, but 300 nm 5-(S)HETE was less effective. The chiral isomer 12-(R)HETE offered no protection; neither did arachidonic acid or 12-(S)hydroperoxyeicosatetraenoic acid. Excitotoxicity was calcium-dependent, and 12-(S)HETE was demonstrated to protect by inactivating N and L (but not P) calcium channels via a pertussis toxin-sensitive mechanism. Calcium imaging demonstrated that 12-(S)HETE also attenuates glutamate-induced calcium influx into neurons via a pertussis toxin-sensitive mechanism, suggesting that it acts via a G-protein-coupled receptor. In addition, 12-(S)HETE stimulates GTPgammaS binding (indicating G-protein activation) and inhibits adenylate cyclase in forskolin-stimulated cultures over the same concentration range as it exerts its anti-excitotoxic and calcium-influx attenuating effects. These studies demonstrate that 12-(S)HETE can protect neurons from excitotoxicity by activating a G(i/o)-protein-coupled receptor, which limits calcium influx through voltage-gated channels.

Citation

Aidan J Hampson, Maurizio Grimaldi. 12-hydroxyeicosatetrenoate (12-HETE) attenuates AMPA receptor-mediated neurotoxicity: evidence for a G-protein-coupled HETE receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2002 Jan 1;22(1):257-64