Cp. Webb et al., INVOLVEMENT OF THE NMDA RECEPTOR IN A NONCHOLINERGIC ACTION OF ACETYLCHOLINESTERASE IN GUINEA-PIG SUBSTANTIA-NIGRA PARS COMPACTA NEURONS, European journal of neuroscience, 8(4), 1996, pp. 837-841
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.