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Dopamine receptor D 3 regulates endocytic sorting by a Prazosin-sensitive interaction with the coatomer COPI

2012; National Academy of Sciences; Volume: 109; Issue: 31 Linguagem: Inglês

10.1073/pnas.1207821109

1091-6490

Xin Zhang, Wenchao Wang, Anne V. Bedigian, Margaret Coughlin, Timothy J. Mitchison, Ulrike Eggert,

Lipid Membrane Structure and Behavior

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.