Cholinergic system Acetylcholine receptors

Figure 5. Cartoon of a cholinergic synapse showing major steps in the synthesis of acetylcholine. The two major receptor types, the ionotropic nicotinic receptor and the metabotropic muscarinic receptor, are shown (see also Chapter 1). Presynaptic muscarinic (M2) and nicotinic receptors are also depicted. Drugs which have been widely used to manipulate the cholinergic systems, and which are mentioned in the text, include the muscarinic receptor antagonists scopolamine and atropine and the nicotinic receptor agonist nicotine. Anticholinesterases (discussed elsewhere in this volume) include drugs such as physostigmine, rivastigmine, donepezil, and galanthamine.

There is considerable diversity among nicotinic acetylcholine receptors, and at least one source of this diversity is the multiplicity of acetylcholine receptor genes. Cholinergic-nicotinic receptors in skeletal muscle are different from those in autonomic ganglia and the central nervous system. 

Q6 In comparison with the sympathetic transmitter norepinephrine, the inactivation of acetylcholine by cholinesterases is rapid so that normally the activity of acetylcholine at the synapse is relatively short-lived. The choline component is taken up into the presynaptic terminal and acetylcholine is resynthesized and stored in the synaptic vesicles. Anticholinesterases function as cholinergic stimulants in the parasympathetic nervous system since they greatly prolong and so increase the actions of endogenous acetylcholine at muscarinic receptors on the effector tissue. 

Sweating is stimulated by direct action of the increased endogenous acetylcholine on muscarinic receptors of sweat glands in the skin these glands are innervated by the sympathetic division of the autonomic nervous system. Agitation is produced by a central excitatory effect on cholinergic neurones in the brain, but in large doses anticholinesterases can cause depression of the respiratory centre in the medulla. 

The nicotinic acetylcholine receptors of the neural excitatory cholinergic system are the targets for both nicotine and neonicotinoids in mammals and insects. 

Some toxic consequences of neonicotinoids for nontarget beneficial aquatic and terrestrial arthropods such as bees can be expected since these creatures have nicotinic acetylcholine receptors as functional components of the cholinergic system similar to those of insect pests. Surprisingly, neonicotinoid toxicity to numerous nontarget insect species and wildlife marker vertebrates, for example, rainbow trout, is lower than expected. In general, the environmental safety of neonicotinoids surpasses that of other insecticides. 

Hint The cholinergic system is another name for the parasympathetic branch because an acetylcholine neurotransmitter stimulates receptor cells to produce a response. The enzyme acetylcholinesterase inactivates the acetylcholine before it reaches the receptor cell. 

Catalpol. Zhang et al. [233] studied the neuroprotective effects of catalpol, an iridoid glycoside isolated from the fresh rehmannia roots, on the cholinergic system and inflammatory cytokines in the senescent mouse brain induced by D-galactose. Acetylcholinesterase (AChE) activity increased in senescent mouse brain and choline acetyltransferase (ChAT) decreased in the basal forebrain of senescent mouse. Muscarinic acetylcholine receptor Ml (mAChRl) expression declined and the levels of tumor necrosis factor (TNF-a), interleukin-ip (IL-ip), and advanced glycation end products... 

Anticholinesterase insecticides phosphorylate the active site of cholinesterase in all parts of the body. Inhibition of this enzyme leads to accumulation of acetylcholine at affected receptors and results in widespread toxicity. Acetylcholine is the neurohormone responsible for physiologic transmission of nerve impulses from preganglionic and postganglionic neurons of the cholinergic (parasympathetic) nervous system, preganglionic adrenergic (sympathetic) neurons, the neuromuscular junction in skeletal muscles, and multiple nerve endings in the central nervous system (Fig. 10-5). 

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