Figure 7.

D2AR and DAT are functionally coupled selectively in the DS, biasing Val559 phenotypic penetrance. A, In WT DS, D2AR control over DAT plays an important role in the termination of DA signaling, in addition to D2AR-induced inhibition of DA synthesis and release. B, Functional D2AR–DAT coupling selectively in the DS results in the upregulation of Val559 DAT regulation desensitization of D2AR coupled to TH, biasing the enhancement of efflux-prone transporters that amplify ADE unabated by D2AR feedback synthesis inhibition, ultimately compromising presynaptic DA signaling. However, at (C) VS DA terminals, DAT lacks D2AR regulation. Hence, (D) despite Val559 expression, the lack of D2AR–DAT coupling in the VS leaves DAT regulation, DA clearance and TH activity unperturbed.