Figure 1.

Overview of the synthesis and regulation of DA. There is evidence that DA is synthesized from tyrosine (Tyr) by a channeling mechanism with the enzymes TH, DDC, and the transporter VMAT2, forming a complex at the vesicular membrane [9,10,11]. The complex, whose details are presently not known, possibly minimizes the oxidations of DA and DOPA by MAO and reactive oxygen species (ROS), respectively [10]. It should however be noted that our analysis does not rely on the existence of such a protein complex. The synthesized DA is stored in synaptic vesicles for release. Significant leakage of transmitter molecules out from vesicles has been observed [16,17,18,19,20], and we tentatively assume that leakage also occurs in vivo. Upon arrival of an action, potential vesicles are emptied, and DA is released into the synaptic cleft. There, DA diffuses to DA-responsive target sites (postsynaptic neurons) or taken up by DA transporters (DAT) at neighboring dopaminergic terminals or metabolizing glial cells [10,14,21]. TH is inhibited both by DA [22,23] and its substrate Tyr [24,25]. There is also an inhibition of TH from extracellular DA via D2 autoreceptors that inhibits stimulatory cAMP/PKA phosphorylation of TH [26,27]. Tyrosinase (TYR) [28,29], converts DOPA to dopaquinone with the final formation of Neuromelanin [30]. Monoamine oxidase (MAO) forms hydrogen peroxide (a reactive oxygen species (ROS)) during the metabolization of DA. ROS are able to oxidize DOPA using a similar pathway as TYR, leading to neuromelanin (see [30] and references therein).