ARACHIDONIC-ACID AS A POSSIBLE NEGATIVE FEEDBACK INHIBITOR OF NICOTINIC ACETYLCHOLINE-RECEPTORS ON NEURONS

Neuronal acetylcholine receptors, being highly permeable to calcium, a re likely to regulate calcium-dependent events in neurons, Arachidonic acid is a membrane-permeant second messenger that can be released fro m membrane phospholipids by phospholipases in a calcium-dependent mann er, We show here that activation of neuronal acetylcholine receptors t riggers release of H-3-arachidonic acid in a calcium-dependent manner from neurons preloaded with the fatty acid, Moreover, low concentratio ns of arachidonic acid reversibly inhibit the receptors and act most e fficiently on receptors likely to have the highest permeability to cal cium, namely receptors containing alpha 7 subunits, Low concentrations of arachidonic acid also reversibly inhibit alpha 7-containing recept ors expressed in Xenopus oocytes following injection of alpha 7 cRNA, The oocyte results indicate that the inhibition is a feature of the re ceptors rather than a consequence of neuron-specific machinery, The in hibition is not mediated by specific metabolites of arachidonic acid b ecause the effects can be mimicked by other fatty acids; their effecti veness correlates with their content of double bonds, In contrast to a rachidonic effects on calcium currents, inhibition of neuronal nicotin ic receptors by the fatty acid cannot be prevented by blocking product ion of free radicals or by inhibiting protein kinase C. An alternative mechanism is that arachidonic acid binds directly to the receptors or perturbs the local environment in such a manner as to constrain recep tor function, The findings indicate that neuronal acetylcholine recept ors, by virtue of their ability to elevate intracellular calcium level s, can release arachidonic acid which is likely to produce a number of secondary effects including feedback inhibition of the receptors.