Effect of tumor necrosis factor-α on the reciprocal G-protein-induced regulation of norepinephrine release by the α₂-adrenergic receptor

α₂-Adrenergic receptors control norepinephrine (NE) release and tumor necrosis factor-α (TNF) production from neurons. TNF regulates NE release, depending on α₂-adrenergic receptor functioning. The relationship between TNF production in the brain and α₂-adrenergic receptor activation could have profound control over NE release. TNF and α₂-adrenergic regulation of NE release was investigated in rat hippocampal slices incubated with pertussis toxin (PTX). The α₂-adrenergic receptor couples to Gα_i/o-proteins to inhibit NE release; however, in slices preexposed to PTX, α₂-adrenergic receptor activation facilitates NE release. TNF exposure subsequent to PTX restores α₂-adrenergic inhibition of NE release. PTX exposure of hippocampal slices prevents agonist-induced increases in Gα_i/o labeling with a GTP analog; after subsequent TNF exposure, agonist-induced increases in Gα_i/o labeling are restored. TNF regulation of NE release transforms from inhibition to facilitation depending on α₂-adrenergic receptor activation following PTX exposure. Therefore, TNF directs the coupling of the α₂-adrenergic receptor, ultimately affecting NE release.