Effect of tumor necrosis factor-alpha on the reciprocal G-protein-induced regulation of norepinephrine release by the alpha2-adrenergic receptor

Alpha2-adrenergic receptors control norepinephrine (NE) release and tumor necrosis factor-alpha (TNF) production from neurons. TNF regulates NE release, depending on alpha2-adrenergic receptor functioning. The relationship between TNF production in the brain and alpha2-adrenergic receptor activation could have profound control over NE release. TNF and alpha2-adrenergic regulation of NE release was investigated in rat hippocampal slices incubated with pertussis toxin (PTX). The alpha2-adrenergic receptor couples to Galpha(i/o)-proteins to inhibit NE release; however, in slices preexposed to PTX, alpha2-adrenergic receptor activation facilitates NE release. TNF exposure subsequent to PTX restores alpha2-adrenergic inhibition of NE release. PTX exposure of hippocampal slices prevents agonist-induced increases in Galpha(i/o) labeling with a GTP analog; after subsequent TNF exposure, agonist-induced increases in Galpha(i/o) labeling are restored. TNF regulation of NE release transforms from inhibition to facilitation depending on alpha2-adrenergic receptor activation following PTX exposure. Therefore, TNF directs the coupling of the alpha2-adrenergic receptor, ultimately affecting NE release.