A fundamental mechanism by which opioid receptors are regulated is by rapid endocytosis after agonistinduced activation. Receptors traverse divergent intracellular membrane pathways after their initial endocytosis, and receptor "sorting" between distinct downstream pathways plays a critical role in determining the functional consequences of endocytosis. The proposed studies seek to elucidate mechanisms that determine whether endocytosed opioid receptors recycle rapidly to the cell surface (a well characterized pathway promoting functional recovery or "resensitization" of signal transduction), or if they traffic to lysosomes (a well established pathway of proteolytic "down-regulation" that leads to a prolonged attenuation of signal transduction).
The Specific Aims of the proposed studies are to: (1) Define the biochemical properties of a mechanism that mediates signal-dependent recycling of opioid receptors;(2) Elucidate a distinct mechanism that promotes sorting of endocytosed opioid receptors to lysosomes;(3) Determine whether opioid receptors are sorted between distinct membrane domains of multivesicular endosomes;and (4) Investigate the functional relevance of specific post-endocytic sorting mechanisms to opioid receptor regulation in neurons. These studies have general relevance to understanding mechanisms by which G protein-coupled receptors are regulated and specific relevance to mechanisms underlying physiological adaptation of the nervous system in response to clinically important opiate drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA010711-15
Application #
8019131
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wu, Da-Yu
Project Start
1997-01-15
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
15
Fiscal Year
2011
Total Cost
$322,413
Indirect Cost
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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) β-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol 18:303-10
Koliwer, Judith; Park, Minjong; Bauch, Carola et al. (2015) The golgi-associated PDZ domain protein PIST/GOPC stabilizes the β1-adrenergic receptor in intracellular compartments after internalization. J Biol Chem 290:6120-9
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; Kotowski, Sarah J; von Zastrow, Mark (2014) Investigating signaling consequences of GPCR trafficking in the endocytic pathway. Methods Enzymol 535:403-18
Irannejad, Roshanak; Tomshine, Jin C; Tomshine, Jon R et al. (2013) Conformational biosensors reveal GPCR signalling from endosomes. Nature 495:534-8
Williams, John T; Ingram, Susan L; Henderson, Graeme et al. (2013) Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65:223-54
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
Just, Sascha; Illing, Susann; Trester-Zedlitz, Michelle et al. (2013) Differentiation of opioid drug effects by hierarchical multi-site phosphorylation. Mol Pharmacol 83:633-9

Showing the most recent 10 out of 30 publications