On the origin and fate of external acetylcholinesterase in peripheral nerve.
1. Rabbit peroneal nerves were exposed to echothiophate, a quaternary ammonium inhibitor of acetylcholinesterase (AChE), and 217-AO, its tertiary analogue, in an attempt to characterize the localization of the enzyme. Although 217-AO readily inhibited AChE throughout the nerves, echothiophate spared significant amounts unless the tissues had first been homogenized. Notably, doses of echothiophate inhibiting 84% of the total AChE inhibited only 30% of the rapidly transported enzyme, suggesting that AChE was distributed between compartments differing greatly in their accessibility to this drug. 2. Since charged molecules penetrate cells poorly, it seemed likely that the more accessible compartment of AChE was external, perhaps consisting mainly of enzyme incorporated into the outer surface of the axolemma. If one assumes that the inhibition of the transported enzyme accurately reflected the inhibition throughout the inaccessible compartment, it can be calculated that external AChE comprised about 80% of the total. 3. The quasi-irreversible inhibition of AChE by echothiophate was used to probe the dynamics of the external enzyme. Locally exposing nerves to this drug in vivo markedly inhibited the AChE in a short region, which subsequently recovered with a half-time of about 5 days. Recovery appeared to reflect delivery of new enzyme into the inhibited region rather than spontaneous reactivation or local synthesis of AChE. Surprisingly, the zone of inhibition neither broadened nor moved noticeably for at least 8 days. This implies that external AChE is largely fixed in place and must be renewed locally, presumably by incorporation of rapidly transported enzyme from the internal compartment.
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D001369:Axons / Q000201:enzymology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004456:Echothiophate Iodide / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D010543:Peroneal Nerve / Q000201:enzymology; D011817:Rabbits
D002800:Cholinesterase Inhibitors; D009946:Organothiophosphorus Compounds; D004456:Echothiophate Iodide; D000110:Acetylcholinesterase