The Molecular Basis of Anticholinesterase Actions on Nicotinic and Glutamatergic Synapses^a

Abstract

INTRODUmIONIn the last 15 years, our knowledge of receptor function has been advanced considerably by studies of the acetylcholine-receptor-ion-channel complex (AChR) of the neuromuscular junction. The Occurrence of nicotinic AChRs at very high densities in Torpedo and Electrophorus electric organs made this membrane receptor easily available for study. In addition, specific chemical probes for the different active sites have contributed significantly to our understanding of the morphology and function of this receptor. In the early 19709, a-bungarotoxin (a-BGT) was isolated from snake venoms and was found to bind irreversibly and specifically to the acetylcholine (ACh) recognition site on the nicotinic AChR.' The availability of such a highly selective probe allowed the isolation, purification, functional reconstitution into artificial lipid membranes, and, ultimately, cloning of the different subunits that comprise the nicotinic AChR.2" The pharmacological characterization of another class of toxins, the histrionicotoxins (HTX), isolated from skin secretions of frogs of the family Dendrobatidae,6*' disclosed an important new class of sites on the nicotinic AChR. These sites, distinct from the agonist recognition site and most likely located on the ion channel component of the AChR, are responsible for allosteric alterations or noncompetitive blockade of neuromuscular transmission. Drugs with distinct and well-

The Pharmacology of Physostigmine

“…Physostigmine exerts stimulating, desensitizing, and blocking actions at nicotinic receptors in addition to its AChE-inhibitory actions at the neuromuscular junction. The agonist effects of physostigmine were observed as early as 1977 (137) and confirmed a number of times (11,202,203,228,233,234). Further support for these actions additional to AChE inhibition, stems from observations that (+) physostigmine, which is virtually devoid of AChE-inhibitory activity, is an agonist at nicotinic acetylcholine receptors (11).…”

“…The agonist effects of physostigmine were observed as early as 1977 (137) and confirmed a number of times (11,202,203,228,233,234). Further support for these actions additional to AChE inhibition, stems from observations that (+) physostigmine, which is virtually devoid of AChE-inhibitory activity, is an agonist at nicotinic acetylcholine receptors (11). Photoaffinity labeling of nicotinic acetylcholine receptors by (+) physostigmine has revealed a pharmacologically distinct drug binding site carried on the same subunit as that for acetylcholine (246).…”

Nicotinic acetylcholine receptors in cultured neurons from the hippocampus and brain stem of the rat characterized by single channel recording

“…Because the individual (+)Antx-induced openings were also shortened, the resulting bursts remained shorter than those activated by ACh. The channel bursts induced in the CNS neurons by (+)Antx at micromolar concentration did not resemble those elicited by desensitizing concentrations of agonists [13,32,37,38], by open channel blockers such as QX222 [39] or anticholinesterase agents such as neostigmine and edrophonium [38]. Rather, as reported for muscles [ 13,401, these fast closures observed with (+ )Antx probably resulted from relatively more rapid transitions from the closed, doubly-agonist-bound state to the opened state as compared to the rates of dissociation of either of two agonist molecules.…”

Effects of organophosphorus anticholinesterases on nicotinic receptor ion channels at adult mouse muscle endplates

“…This idea seems more likely, as the lone pair of electrons on the tertiary nitrogen atom of VX makes it susceptible to protonation (Epstein et al, 1974 (Albuquerque et al, 1985;Rao et al, 1987;Aracava et al, 1988). VX has also been reported to be a potent inhibitor of [3H]-perhydrohistrionicotoxin binding to the nicotinic cholinoceptor ion channel in both closed and open states, but predominantly in the latter (Eldefrawi et al, 1985).…”