INHIBITION OF ANTAGONIST AND AGONIST BINDING TO THE HUMAN BRAIN MUSCARINIC RECEPTOR BY ARACHIDONIC-ACID

Arachidonic acid (AA) inhibits the binding of [H-3]quinclidinyl benzil ate ([H-3]QNB) to the human brain muscarinic cholinergic receptor (mAC hR). AA inhibits at lower concentrations in the absence of glutathione (I-50 = 15 mu M) than in the presence of glutathione (I-50 = 42 mu M) Inhibition of mAChR binding shows specificity for AA and is reduced w ith loss of one or more double bonds or with either a decrease or incr ease in the length of the fatty acid chain. Metabolism of AA by the li poxygenase, epoxygenase, or fatty acid cyclooxygenase pathways is not required for the inhibitory activity of AA on mAChR binding. Inhibitio n of [H-3]QNB binding by AA is reversible. While decreasing B-max, AA increased the apparent K-D for [H-3]QNB and for the more polar antagon ist [H-3]NMS. In addition, AA inhibits binding of the agonist [H-3]oxo tremorine-M (I-50 = 60 mu M) and is the first mediator of mAChR action to be shown to reversibly inhibit mAChR binding. The feedback inhibit ion of the mAChR by AA may serve a homeostatic function similar to the reuptake and hydrolysis of acetylcholine following cholinergic nerve transmission.