FIGURE 20-1 Production of free radicals by the metabolism of dopamine. Dopamine is converted by monamine oxidase (MAO) and aldehyde dehydrogenase (AD) to 3,4-dihydroxyphenylacetic acid (DOPAC), producing hydrogen peroxide (H2O2). In the presence of ferrous iron, H2O2 undergoes spontaneous conversion, forming a hydroxyl-free radical (the Fenton reaction).
DOPAMINE SYNTHESIS, METABOLISM, AND ACTION
Dopamine, a catecholamine, is synthesized in the terminals of dopaminergic neurons from tyrosine and stored, released, and metabolized by processes described in Chapter 6 and summarized in Figures 20-2 and 20—3. The actions of dopamine in the brain are mediated by dopamine receptors, all of which are heptahelical G protein-coupled receptors (GPCRs) (see Chapter 1). The five dopamine receptors can be divided into two groups on the basis of their pharmacological and structural properties (Figure 20-4). The D1 and D5 proteins have a long intracellular carboxy-terminal tail and are members of the class defined pharmacologically as D1; they stimulate the formation of cyclic AMP and phosphatidyl inositol hydrolysis. The D2, D3, and D4 receptors share a large third intracellular loop and are of the D2 class. They decrease cyclic AMP formation and modulate K+ and Ca2+ currents. Each of the five dopamine receptor proteins has a distinct anatomical distribution in the brain. The D1 and D2 proteins are abundant in the striatum and are the most important receptor sites with regard to the causes and treatment of PD. The D4 and D5 proteins are largely extrastriatal, whereas D3 expression is low in the caudate and putamen but more abundant in the nucleus accumbens and olfactory tubercle.
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