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 #
1R29DA010711-01
Application #
2013772
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Rasooly, Rebekah S
Project Start
1997-01-15
Project End
2001-11-30
Budget Start
1997-01-15
Budget End
1997-11-30
Support Year
1
Fiscal Year
1997
Total Cost
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
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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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