Dopamine receptor D3 regulates endocytic sorting by a Prazosin-sensitive interaction with the coatomer COPI.
Macromolecules enter cells by endocytosis and are sorted to different cellular destinations in early/sorting endosomes. The mechanism and regulation of sorting are poorly understood, although transitions between vesicular and tubular endosomes are important. We found that the antihypertensive drug Prazosin inhibits endocytic sorting by an off-target perturbation of the G protein-coupled receptor dopamine receptor D(3) (DRD3). Prazosin is also a potent cytokinesis inhibitor, likely as a consequence of its effects on endosomes. Prazosin stabilizes a normally transient interaction between DRD3 and the coatomer COPI, a complex involved in membrane transport, and shifts endosomal morphology entirely to tubules, disrupting cargo sorting. RNAi depletion of DRD3 alone also inhibits endocytic sorting, indicating a noncanonical role for a G protein-coupled receptor. Prazosin is a powerful tool for rapid and reversible perturbation of endocytic dynamics.
Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Xin
X
Zhang
Wenchao
W
Wang
Anne V
AV
Bedigian
Margaret L
ML
Coughlin
Timothy J
TJ
Mitchison
Ulrike S
US
Eggert
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects / Q000235:genetics; D020755:Coat Protein Complex I / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects* / Q000235:genetics; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D011224:Prazosin / Q000494:pharmacology*; D055550:Protein Stability / Q000187:drug effects; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism*
D058668:Adrenergic alpha-1 Receptor Antagonists; D020755:Coat Protein Complex I; C493593:DRD3 protein, human; D050637:Receptors, Dopamine D3; D011224:Prazosin