Molecular and cellular biology of cholinesterases

Synaptic structure and development: the neuromuscular junction.

The mechanism of cholinergic neurotransmission requires the rapid inac­ tivation of acetylcholine (Dale 1914). Loewi & Navratil showed in 1926 that acetylcholine can be destroyed by an enzyme that exists in aqueous extracts of frog tissues. An esterase that specifically hydrolyzes choline esters was characterized in horse serum by Stedman et al (1932), who called it choli­ nesterase. It was later found that blood cells also contain a high level of acetylcholine-hydrolyzing activity (Stedman & Stedman 1935). Alles & Hawes (1940) subsequently found that in human blood the serum and cell enzymes are qualitatively different; Mendel et al (1943a) showed that, al­ though the serum enzyme hydrolyzes butyrylcholine or propionylcholine faster than acetylcholine [as already noted by Stedman et al (1932)], the cell-bound enzyme acts preferentially on acetylcholine, at low substrate concentration. The particulate enzyme also presents a characteristic excess substrate inhibition, so that its activity varies, in a bell-shaped manner, as a function of substrate concentration (Mendel & Rudney 1943). These two activities exist in all classes of vertebrates. The serum enzyme (Be 3.1.1.8) varies somewhat in its specificity, notably in the relative rates of hydrolysis of propionylcholine and butyrylcholine (Augustinsson 1959a,b). The serum enzyme was called originally "nonspecific" cholineste­ rase, or "pseudocholinesterase" (Mendel et al 1943, Mendell & Rudney 1943). In contrast, the erythrocyte enzyme (EC 3.1.1.7) was considered the

The Molecular Forms of Cholinesterase and Acetylcholinesterase in Vertebrates

Innervation of muscle by motoneurones induces the development of a characteristic, high density cluster of acetylcholine receptors (AChRs) at the neuromuscular junction. Studies in vitro show that the accumulation of AChRs at nerve-muscle contacts results from both increased insertion of new AChRs into the muscle plasma membrane beneath nerve terminals and redistribution of preexisting AChRs; these two modes of AChR accumulation may be separately controlled since factors have been identified that influence AChR redistribution but not synthesis. Although many aspects of muscle development are regulated by nerve-dependent muscle activity, junctional AChR clusters still develop when neuromuscular transmission is blocked by either curare or alpha-bungarotoxin, suggesting that their formation is mediated by nerve-derived trophic factors other than activity. A molecule immunologically related to calcitonin gene-related peptide (CGRP-I) has been found in motoneurones in a variety of mammals including man. Here we provide indirect evidence that CGRP-I may be a motoneurone-derived trophic factor that increases AChR synthesis at vertebrate neuromuscular junctions.

Calcitonin gene-related peptide regulates muscle acetylcholine receptor synthesis.

Roles of neurotransmitter in synapse formation: development of neuromuscular junctions lacking choline acetyltransferase.

The appearance of acetylcholinesterase (AChE) at newly formed nerve–muscle synapses depends on synaptic transmission. Synapses form when cultures are grown in the presence of acetylcholine receptor antagonists, but AChE does not accumulate at these synapses. The important component of transmission seems to be muscle activity. Treatment with dibutyryl cyclic GMP mimics muscle activity, directly inducing synaptic AChE appearance.

Stephen M. Schuetze

Papers

Regulation of acetylcholinesterase appearance at neuromuscular junctions in vitro