Dopamine D2 autoreceptor interactome: Targeting the receptor complex as a strategy for treatment of substance use...

Dopamine D2 autoreceptors (D₂ARs), located in somatodendritic and axon terminal compartments of dopamine (DA) neurons, function to provide a negative feedback regulatory control on DA neuron firing, DA synthesis, reuptake and release. Dysregulation of D₂AR-mediated DA signaling is implicated in vulnerability to substance use disorder (SUD). Due to the extreme low abundance of D₂ARs compared to postsynaptic D₂ receptors (D₂PRs) and the lack of experimental tools to differentiate the signaling of D₂ARs from D₂PRs, the regulation of D₂ARs by drugs of abuse is poorly understood. The recent availability of conditional D₂AR knockout mice and newly developed virus-mediated gene delivery approaches have provided means to specifically study the function of D₂ARs at the molecular, cellular and behavioral levels. There is a growing revelation of novel mechanisms and new proteins that mediate D₂AR activity, suggesting that D₂ARs act cooperatively with an array of membrane and intracellular proteins to tightly control DA transmission. This review highlights D₂AR-interacting partners including transporters, G-protein-coupled receptors, ion channels, intracellular signaling modulators, and protein kinases. The complexity of the D₂AR interaction network illustrates the functional divergence of D₂ARs. Pharmacological targeting of multiple D₂AR-interacting partners may be more effective to restore disrupted DA homeostasis by drugs of abuse.