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

Xin Zhang; Wenchao Wang; Anne V. Bedigian; Margaret L. Coughlin; Timothy J. Mitchison; Ulrike S. Eggert

doi:10.1073/pnas.1207821109

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

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

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	12485-12490
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	31
DOIs	https://doi.org/10.1073/pnas.1207821109
Publication status	Published - 31 Jul 2012

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

abstract = "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.",

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T1 - Dopamine receptor D-3 regulates endocytic sorting by a Prazosin-sensitive interaction with the coatomer COPI

AU - Zhang, Xin

AU - Wang, Wenchao

AU - Bedigian, Anne V.

AU - Coughlin, Margaret L.

AU - Mitchison, Timothy J.

AU - Eggert, Ulrike S.

PY - 2012/7/31

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AB - 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.

U2 - 10.1073/pnas.1207821109

DO - 10.1073/pnas.1207821109

M3 - Article

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

Abstract

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