Mechanisms that regulate opioid receptors play important roles in opiate drug action and are of fundamental importance to the biology of addiction. The proposed studies focus on the regulation of opioid receptors by rapid endocytosis. This process is of particular interest because (a) it distinguishes between structurally homologous types of cloned opioid receptor (delta, mu, and kappa); and (b) it is differentially regulated by opioid peptides and morphine. I propose to elucidate molecular mechanisms that mediate and regulate opioid receptor endocytosis, with the goal of understanding the remarkable type-selectivity and ligand-specificity of this process.
The Specific Aims of the proposed studies are (1) to define endocytotic mechanisms that determine the type-selectivity and ligand-specificity of opioid receptor endocytosis, (2) to identify receptor domains that mediate type-selective differences in the endocytosis of cloned opioid receptors, and (3) to examine the effect of protein phosphorylation sites on type-selective and ligand-specific endocytosis of opioid receptors. These studies are directly relevant to the biology of opiate action and addiction. In addition, because the ability of different full agonist ligands to differentially regulate receptor endocytosis is a novel finding, these studies have general importance to the cell biology of G protein-coupled receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA010711-05
Application #
6329149
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Koustova, Elena
Project Start
1997-01-15
Project End
2003-11-30
Budget Start
2000-12-10
Budget End
2001-11-30
Support Year
5
Fiscal Year
2001
Total Cost
$101,579
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Irannejad, Roshanak; Pessino, Veronica; Mika, Delphine et al. (2017) Functional selectivity of GPCR-directed drug action through location bias. Nat Chem Biol 13:799-806
Tsvetanova, Nikoleta G; Trester-Zedlitz, Michelle; Newton, Billy W et al. (2017) G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands. Mol Pharmacol 91:145-156
Lobingier, Braden T; Hüttenhain, Ruth; Eichel, Kelsie et al. (2017) An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells. Cell 169:350-360.e12
Uchida, Yasunori; Rutaganira, Florentine U; Jullié, Damien et al. (2017) Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling. Mol Pharmacol 91:65-73
Varandas, Katherine C; Irannejad, Roshanak; von Zastrow, Mark (2016) Retromer Endosome Exit Domains Serve Multiple Trafficking Destinations and Regulate Local G Protein Activation by GPCRs. Curr Biol 26:3129-3142
Eichel, K; Jullié, D; von Zastrow, M (2016) ?-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol 18:303-10
Leaf, Alison; Von Zastrow, Mark (2015) Dopamine receptors reveal an essential role of IFT-B, KIF17, and Rab23 in delivering specific receptors to primary cilia. Elife 4:
Tsvetanova, Nikoleta G; von Zastrow, Mark (2014) Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis. Nat Chem Biol 10:1061-5
Irannejad, Roshanak; Tomshine, Jin C; Tomshine, Jon R et al. (2013) Conformational biosensors reveal GPCR signalling from endosomes. Nature 495:534-8
Marley, Aaron; Choy, Regina Wai-Yan; von Zastrow, Mark (2013) GPR88 reveals a discrete function of primary cilia as selective insulators of GPCR cross-talk. PLoS One 8:e70857

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