Figure 5.

Reaction scheme of the TH-DA negative feedback model with added rate constants and fluxes. Not all DOPA and DA are necessarily bound to the channeling complex, but since the complex is not evenly distributed within the cytoplasm, both cytosolic DOPA and DA are considered to be located proximate to the complex. With increasing age and increased MAO levels [74] MAO may oxidize DA and perturb the feedback control of DOPA (path outlined in gray). In addition, both DOPA and DA are subject to auto-oxidation [75,76], which are included in the model by $k_{14}$ (together with ROS) and $\alpha (k_{18}, k_{19})$ (together with MAO). As in Figure 3, pairs of rate constants ($k_i$, $k_j$) represent the respective ($V_{max}$, $K_M$) values of applied Michaelis–Menten kinetics. With increased MAO concentrations, oxidative stress and ROS also increase due to MAO-generated hydrogen peroxide. ROS can oxidize DOPA [30] (outlined in red). Cytosolic DA concentration is increased due to the re-entry of DA (flux $j_{11}$) and by vesicular leakage [16,17,18,19,20] (flux $j_{23}$). Inflow of Ca${}^{2+}$ by neuronal stimulation lead to release of vesicular DA into the synaptic cleft. Clearance of DA in the synaptic cleft occurs by diffusion, glial cell metabolization [14,21], or uptake of DA by DAT [77,78].