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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wu, Da-Yu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
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
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
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
Koliwer, Judith; Park, Minjong; Bauch, Carola et al. (2015) The golgi-associated PDZ domain protein PIST/GOPC stabilizes the ?1-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:
Irannejad, Roshanak; Kotowski, Sarah J; von Zastrow, Mark (2014) Investigating signaling consequences of GPCR trafficking in the endocytic pathway. Methods Enzymol 535:403-18
Tsvetanova, Nikoleta G; von Zastrow, Mark (2014) Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis. Nat Chem Biol 10:1061-5

Showing the most recent 10 out of 37 publications