RT Journal Article
SR Electronic
T1 Identification of Two Functionally Distinct Endosomal Recycling Pathways for Dopamine D<sub>2</sub> Receptor
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7178
OP 7190
DO 10.1523/JNEUROSCI.0008-12.2012
VO 32
IS 21
A1 Yun Li
A1 Brittany D. Roy
A1 Wei Wang
A1 Li Zhang
A1 Lifeng Zhang
A1 Stephen B. Sampson
A1 Yupeng Yang
A1 Da-Ting Lin
YR 2012
UL http://www.jneurosci.org/content/32/21/7178.abstract
AB Dopamine D2 receptor (DRD2) is important for normal function of the brain reward circuit. Lower DRD2 function in the brain increases the risk for substance abuse, obesity, attention deficit/hyperactivity disorder, and depression. Moreover, DRD2 is the target of most antipsychotics currently in use. It is well known that dopamine-induced DRD2 endocytosis is important for its desensitization. However, it remains controversial whether DRD2 is recycled back to the plasma membrane or targeted for degradation following dopamine stimulation. Here, we used total internal reflection fluorescent microscopy (TIRFM) to image DRD2 with a superecliptic pHluorin tagged to its N terminus. With these technical advances, we were able to directly visualize vesicular insertion events of DRD2 in cultured mouse striatal medium spiny neurons. We showed that insertion of DRD2 occurs on neuronal somatic and dendritic surfaces. Lateral diffusion of DRD2 was observed following its insertion. Most importantly, using our new approach, we uncovered two functionally distinct recycling pathways for DRD2: a constitutive recycling pathway and a dopamine activity-dependent recycling pathway. We further demonstrated that Rab4 plays an important role in constitutive DRD2 recycling, while Rab11 is required for dopamine activity-dependent DRD2 recycling. Finally, we demonstrated that the two DRD2 recycling pathways play distinct roles in determining DRD2 function: the Rab4-sensitive constitutive DRD2 recycling pathway determines steady-state surface expression levels of DRD2, whereas the Rab11-sensitive dopamine activity-dependent DRD2 recycling pathway is important for functional resensitization of DRD2. Our findings underscore the significance of endosomal recycling in regulation of DRD2 function.