| Anatomy | Cell Biology | Physiology | Behavior and Clinical |
ACh binds only briefly to the pre- or postsynaptic receptors. Following dissociation from the receptor, the ACh is rapidly hydrolyzed by the enzyme acetylcholinesterase (AChE) as shown in Figure 11.14. This enzyme has a very high catalysis rate, one of the highest known in biology. AChE is synthesized in the neuronal cell body and distributed throughout the neuron by axoplasmic transport. AChE exists as alternatively spliced isoforms that vary in their subunit composition. The variation at the NMJ is a heteromeric protein composed of four subunits coupled to a collagen tail that anchors the multi-subunit enzyme to the cell membrane of the postsynaptic cell (Figure 11.14). This four-subunit form is held together by sulfhydryl bonds and the tail anchors the enzyme in the extracellular matrix at the NMJ. Other isoforms are homomeric and freely soluble in the cytoplasm of the presynaptic cell. AChE, unlike ChAT, is found in non-cholinergic neurons as well. In addition, other cholinesterases exist throughout the body, which are also able to metabolize acetylcholine. These are termed pseudocholinesterases.
Figure 11.14 |
Drugs that inhibit ACh breakdown are effective in altering cholinergic neurotransmission. In fact, the irreversible inhibition of AChE by isopropylfluoroesters are so toxic that they can be incompatible with life—inhibiting the muscles for respiration. This inhibition is produced because ACh molecules accumulate in the synaptic space, keep the receptors occupied, and cause paralysis. Two notable examples are insecticides and the gases used in biological warfare. The mechanism of action of these irreversible inhibitors of AChE is that they carbamylate the AChE, rendering it inactive. The carbamylation inactivates both the acetyl and choline binding domains. A recently developed antidote to these inhibitors cleaves the nerve gas so that it will dissociate from the AChE.
In contrast to the irreversible inhibitors, the reversible AChE inhibitors are effective in transiently increasing the ACh level and are effective in diseases and conditions where an increased ACh level is desired. The clinically important compound, eserine (physostigmine), reversibly inhibits AChE.
