(A) Presynaptic and postsynaptic neuron membranes and the synaptic cleft are indicated. D1-class and D2-class dopamine receptors are positively or negatively coupled to adenylate cyclase (AC) via G proteins (G). Coupling to other signaling pathways is not shown. Catechol O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) are involved in the metabolism of dopamine (blue circles) to products such as homovanillic acid (HVA) and 3-methoxytyramine (3-MT). Dopamine in the cleft can bind presynaptically to D2 autoreceptors or the DAT, or postsynaptically to D1- and D2-class receptors. The DAT is predominately located perisynaptically. (B) In this issue of the JCI, Kurian et al. (14) show that SLC6A3/DAT1 loss-of-function mutations in individuals with infantile parkinsonism-dystonia result in inhibition of DAT-mediated dopamine reuptake activity. Increased time that dopamine is present in the synaptic cleft will result in dopamine degradation there, predominantly by COMT, as well as increased levels of the dopamine metabolite homovanillic acid in the cerebrospinal fluid. Overstimulation of D2 autoreceptors is predicted to inhibit the phosphorylation-dependent activation of tyrosine hydroxylase (TH), which is rate limiting for the production of dopamine. Mutations in the gene encoding TH have been implicated in other movement disorders such as L-dopa–responsive dystonia and infantile parkinsonism. Prolonged dopamine presence in the synaptic cleft may result in desensitization or downregulation of postsynaptic dopamine receptors, with alterations in downstream signaling.