INVOLVEMENT OF THE NMDA RECEPTOR IN A NONCHOLINERGIC ACTION OF ACETYLCHOLINESTERASE IN GUINEA-PIG SUBSTANTIA-NIGRA PARS COMPACTA NEURONS

Evidence is accumulating that a soluble, secretory form of acety]choli nesterase may have novel, non-cholinergic functions in certain brain r egions, such as the substantia nigra. In this study, application of hu man recombinant acetylcholinesterase (rhAChE) to pars compacta neurons in the rostral substantia nigra resulted in a sustained hyperpolariza tion that was not only mimicked by application of N-methyl-D-aspartate (NMDA) but also blocked by the NMDA receptor antagonists MK801 and 2- amino-5-phosphonopentanoic acid. Neither the rhAChE- nor the NMDA-indu ced hyperpolarization was seen when the calcium chelator BAPTA was inj ected into the neuron; hence the effect is mediated by accumulation of intracellular calcium. This intracellular calcium appears sufficient to compromise neuronal metabolism since the rhAChE-induced hyperpolari zation was reversed by application of the K-ATP channel antagonist tol butamide. Butyrylcholinesterase, a protein of similar molecular weight to acetylcholinesterase, which also hydrolyses acetylcholine, had no effect whatsoever. The results suggest that, independent of its normal catalytic function, acetylcholinesterase can act via the NMDA recepto r complex to enhance calcium entry into nigral neurons and jeopardize cell metabolism. This non-classical action of acetylcholinesterase mig ht thus be an important factor in the mechanisms underlying parkinsoni an neurodegeneration.