FIGURE 6–5 Biosynthesis of catecholamines. The rate-limiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (α-methyltyrosine). The alternative pathway shown by the dashed arrows has not been found to be of physiologic significance in humans. However, tyramine and octopamine may accumulate in patients treated with monoamine oxidase inhibitors. (Reproduced, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.)
Termination of noradrenergic transmission results from two processes: simple diffusion away from the receptor site (with eventual metabolism in the plasma or liver) and reuptake into the nerve terminal by NET (Figure 6–4) or into perisynaptic glia or other cells.
As previously noted, the vesicles of both cholinergic and adrenergic nerves contain other substances in addition to the primary transmitter, sometimes in the same vesicles and sometimes in a separate vesicle population. Some of the substances identified to date are listed in Table 6–1. Many of these substances are also primary transmitters in the nonadrenergic, noncholinergic nerves described in the text that follows. They appear to play several roles in the function of nerves that release acetylcholine or nor-epinephrine. In some cases, they provide a faster or slower action to supplement or modulate the effects of the primary transmitter. They also participate in feedback inhibition of the same and nearby nerve terminals.
Growth of neurons and transmitter expression in specific neurons is a dynamic process. For example, neurotrophic factors released from target tissues influence growth and synapse formation by neurons. In addition, the transmitters released from a
FIGURE 6–6 Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). (Reproduced, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.) specific population of neurons can change in response to environmental factors such as the light-dark cycle.
Historically, structure-activity analyses, with careful comparisons of the potency of series of autonomic agonist and antagonist analogs, led to the definition of different autonomic receptor subtypes, including muscarinic and nicotinic cholinoceptors, and α, β, and dopamine adrenoceptors (Table 6–2). Subsequently, binding of isotope-labeled ligands permitted the purification and characterization of several of the receptor molecules. Molecular biology now provides techniques for the discovery and expression of genes that code for related receptors within these groups (see Chapter 2).
The primary acetylcholine receptor subtypes were named after the alkaloids originally used in their identification: muscarine and nicotine, thus muscarinic and nicotinic receptors. In the case of receptors associated with noradrenergic nerves, the use of the names of the agonists (noradrenaline, phenylephrine, isoproterenol, and others) was not practicable. Therefore, the term adrenoceptor is widely used to describe receptors that respond to catecholamines such as norepinephrine. By analogy, the term cholinoceptor denotes receptors (both muscarinic and nicotinic) that respond to acetylcholine. In North America, receptors were colloquially named after the nerves that usually innervate them; thus,
CHAPTER 6 Introduction to Autonomic Pharmacology
TABLE 6–2 Major autonomic receptor types.
1Cardiac β3-receptor function is poorly understood, but activation does not appear to result in stimulation of rate or force.