UCSF

Regulation of Dopamine Signaling by D₁ Receptor Membrane Trafficking

Dopamine is a major catecholamine neurotransmitter in the central nervous system (CNS). Dopaminergic signaling is a critical component of a number of complex physiological functions including movement, learning and memory, attention and goal-directed behaviors. The cellular actions of dopamine are mediated by a family of G protein-coupled receptors (GPCRs), the dopamine receptors. The D₁ receptor is the major excitatory transducer of dopaminergic signaling within the brain. In this study, we examine the contribution of D₁ receptor membrane trafficking to the regulation of dopaminergic signaling in a HEK 293 model system, as well as in cortical and striatal neurons known to natively express D₁ receptors. We find that D₁ receptor membrane trafficking does not play a significant role in determining cellular sensitivity to dopamine after prolonged (30 minutes to 1 hour) agonist incubation. However, when we examine D₁ receptor trafficking and signaling with much greater temporal resolution, we find that rapid endocytosis is essential for neuronal dopamine signaling. Further, the kinetics of this regulation approaches those of transient increases in extracellular dopamine observed within the intact brain. This body of work presents a novel, and previously unanticipated role for endocytosis in the regulation of D₁ receptor-mediated dopaminergic signaling in neurons.