Fig. 1.

Regulation of DAT phosphorylation. AMPH acts as a substrate for DAT (orange oval) and is transported into the neuron (dashed arrow pointing intracellularly), which leads to an increase in intracellular Ca²⁺ levels, an increase in CaMKIIα and PKC activity, and an increase in the levels of DAT phosphorylation, all of which have been demonstrated to facilitate AMPH-induced DAT-mediated DA efflux (dashed arrow pointing extracellularly). Activation of PKC by the phorbol ester PMA also increases DAT phosphorylation, as does inhibition of protein phosphatases by okadaic acid (OA). The mechanistic relationship between CaMKII and PKC, with respect to DAT phosphorylation, remains unclear (as indicated by the question mark). Localization of DAT to cholesterol-rich membrane microdomains (purple section of plasma membrane) facilitates its phosphorylation in response to AMPH, and thereby the consequent DA efflux and associated behaviors.