Neurochemical Basis of Adrenergic Transmission

Tyrosine is converted to dopa by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin, and is inhibited by a-methyltyrosine. Dopa is decarboxylated to dopamine by L-aromatic amino acid decarboxylase, which requires pyridoxal phosphate (vitamin B6) as a coenzyme. Carbidopa, which is used with levodopa in the treatment of parkinsonism, inhibits this enzyme. Dopamine is converted to norepinephrine by dopamine P-hydroxylase, which requires ascorbic acid (vitamin C), and is inhibited by diethyldithiocarbamate. Norepinephrine is converted to epinephrine by phenylethanolamine A -methyltransferase (PNMT), requiring S-adeno-sylmethionine. The activity of PNMT is stimulated by corticosteroids. 

The catecholamine-synthesizing enzymes are not only able to synthesize dopamine and norepinephrine from a physiologically occurring substrate such as levodopa, but also from exogenous substrates such as a-methyldopa, which is converted to a-methyldopamine and in turn to a-methylnorepinephrine. a-methyldopamine and a-methylnorepinephrine are called false transmitters and, in general (except for a-methylnorepinephrine), are weaker agonists, a-methyldopa is used in the management of hypertension. 

In addition to being synthesized in the peripheral nervous system, dopamine is synthesized in the corpus striatum and in the mesocortical, mesolimbic, and tuberoinfundibular systems. Norepinephrine is synthesized and stored primarily in sympathetic noradrenergic nerve terminals, as well as in the brain and the adrenal medulla. Epinephrine is synthesized and stored primarily in the adrenal medulla and, to a certain extent, in the hypothalamic nuclei. 

In sympathetic nerve terminals, as well as the brain, the adrenal medulla, and sympathetic postganglionic terminals, there are osmophilic granules (synaptic vesicles) that are capable of storing high concentrations of catecholamine (a complex with adenosine triphosphate, or ATP, and protein). The stored amines are not metabolized by the intersynaptosomal mitochondrial enzyme (monoamine oxidase). 

In addition to releasing norepinephrine (through exocytosis), the stimulation of sympathetic neurons also releases ATP, storage protein, and dopamine P-hydroxylase. The released norepinephrine interacts with receptor sites located postsynaptically (a,) to produce the desired effects. 

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