Neurotransmitters and receptors

There are an enormous number of neurotransmitters, including amino acids and derivatives, amines, peptides and acetylcholine. Much of the diversity of transmitters occurs within the CNS, and also within the enteric nervous system. With regard to metabolic regulation, we will be considering mainly adrenergic and cholinergic transmission.

Sarcolemma of the muscle fibre

Myofibrils

Fig. 7.4 The neuromuscular junction.

Sarcolemma of the muscle fibre

Myofibrils

Fig. 7.4 The neuromuscular junction.

7.2.3.1 Adrenergic transmission

The pathway for synthesis of noradrenaline and adrenaline was shown in Fig. 5.10. Dopamine (the biosynthetic precursor of noradrenaline) is also a neurotransmitter in the CNS. The sympathetic nerve terminals release noradrenaline, although a small amount of dopamine (present in the secretory vesicles) is co-secreted. The adrenal medulla is, in effect, a modification of a postganglionic neuron - it is, as we have seen, stimulated by a (cholinergic) preganglionic fibre, and has evolved to secrete the hormone adrenaline into the bloodstream rather than noradrenaline into a synaptic cleft. Note from Fig. 5.10 that adrenaline is one biosynthetic step beyond noradrenaline.

Adrenaline and noradrenaline, which are similar in structure, act through the same receptors, in a molecular sense. It is probable, however, that some receptors (for instance, those on the receiving side of a synaptic cleft) will only 'see' noradrenaline, whereas others more exposed to the circulation will respond to adrenaline carried in the blood. After noradrenaline has been liberated into the synaptic cleft, it is rapidly taken up again, both back into the synaptic terminal (for recycling) and into other tissues. However, a proportion 'escapes' re-uptake and enters the extracellular fluid, and thence the plasma. The concentration of noradrenaline in the plasma is, in fact, usually higher than that of adrenaline, although it is only there through this 'spillover' effect. The concentration of noradrenaline in plasma gives an indication of the overall activity of the sympathetic nervous system in the body. (This concept can even be refined. It is possible to show release of noradrenaline from the muscle of the forearm, for instance, by measurement of the concentrations in the artery supplying, and in a vein draining this muscle. It has been shown that noradrenaline release correlates with the activity of the sympathetic nerves supplying this muscle, measured by micro-electrodes applied to the nerves.)

The two broad subtypes of adrenergic receptors, known as a and P, and the subdivisions of these receptors, were discussed in connection with adrenaline action in Section 5.5.2 and Table 5.1.

7.2.3.2 Cholinergic transmission

Acetylcholine (Fig. 7.2) is synthesised from acetyl-CoA and choline. After its release from cholinergic nerve endings, acetylcholine is rapidly degraded (into choline and acetate) by the enzyme acetylcholinesterase, which is present on the postsynaptic membrane. The choline is taken up again by the nerve terminal for synthesis of more acetylcholine. A large group of pesticides, the organophosphorus esters, act by binding to the enzyme acetylcholinesterase, and thus causing excessive accumulation of acetylcholine. They are, of course, toxic to humans by exactly the same mechanism, and lead to muscle paralysis, with death eventually from respiratory paralysis. The effects can be reversed to some extent with atropine.

Recognition that there are two main types of cholinergic receptors was one of the early triumphs of experimental pharmacology. Dale in 1914

showed that there were some actions of acetylcholine which could be mimicked by administration of muscarine, the active component of the poisonous mushroom Amanita muscaria; these effects were abolished by small doses of atropine. They correspond roughly to the effects of the parasympathetic nervous system. Other effects of acetylcholine were still apparent after blockade with muscarine, and these were similar to the effects of nicotine (the active component of tobacco). The effects produced by nicotine included stimulation of the contraction of skeletal muscle, and the release of adrenaline from the adrenal medulla. We now recognise that these effects are mediated through two specific types of acetylcholine receptor, the muscarinic receptor and the nicotinic receptor. Both nicotinic and muscarinic receptors have since been further subdivided on the basis of cloning of homologous receptor proteins. Cholinergic synapses within the central nervous system are nicotinic; outside the central nervous system they are mostly muscarinic at target organs, unless they are preganglionic fibres.

The function of the two types of receptor, together with noradrenaline, in the central and peripheral nervous systems is illustrated in Fig. 7.5.

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