The search for the physiological functions of NTE; is NTE a receptor?
Neuropathy target esterase (NTE) was identified as the molecular target for organophosphate-induced delayed polyneuropathy several years ago but its physiological functions are still unknown. The mechanism which initiates neuropathy was thought to be a two step process: inhibition (phosphorylation) of NTE and aging of phosphorylated NTE. Depending on the occurrence of the second reaction (aging), inhibitors were ranked as neuropathic (forming an ageable NTE) and non-neuropathic (forming a non-ageable NTE). Non-neuropathic inhibitors protect from neuropathy if given before the neuropathic ones, because they occupy the catalytic centre of NTE. Thus the catalytic function of NTE seems irrelevant in maintaining the health of neurons. This paper reviews some new information concerning the interaction of NTE with its inhibitors as well as on a phenomenon called promotion of neuropathy. Some inhibitors which apparently form a non-ageable inhibited NTE were found to cause neuropathy, even though some of them must be given at very high doses. Moreover some 'non-neuropathic-protective' NTE inhibitors were found to exacerbate (promote) neuropathy when given after a neuropathic one. It is likely that the target for promotion is other than NTE. The hypothesis that NTE has some unknown receptorial functions where inhibitors act with different efficacy is discussed. NTE inhibitors have been ranked as full agonists (classic neuropathic inhibitors such as diisopropylfluorophosphate), partial agonists (protective or neuropathic, depending on the dose, such as methamidophos) and antagonists (protective, and neuropathic at the highest doses, such as phenylmethanesulfonyl fluoride). Age-related differences in the 'receptor' NTE might be responsible for the different sensitivities of juvenile and adult animals.
Universita' degli Studi di Padova, Istituto di Medicina del Lavoro, Italy.
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Lotti
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Moretto
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*
D011956:Receptors, Cell Surface; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase