Endocytosis of opioid receptors modulates signal transduction and is thought to be involved in opiate drug action and addiction. This process is highly regulated by ligands, both in cultured cells and native tissues. A phosphorylation-dependent mechanism that promotes receptor endocytosis has been described previously. Preliminary studies suggest the hypothesis that additional mechanisms contribute to the physiological regulation of opioid receptor endocytosis observed in intact cells. Furthermore, the preliminary data suggest that these mechanisms are relevant to opiod receptor regulation in neurons. The proposed studies test this hypothesis by focusing on two distinct mechanisms, which have opposite effects on receptor endocytosis and differ in their dependence on receptor phosphorylation. The proposed experiments seek to elucidate these mechanisms in biochemical detail, identify cellular proteins that mediate them, and examine their functional consequences in neurons.
The Specific Aims are to (1) characterize a mechanism that promotes rapid endocytosis of a truncated, phosphorylation-deficient mutant opioid receptor; (2) characterize a phosphorylation-regulated mechanism that inhibits endocytosis of full-length opioid receptors; and (3) identify cellular proteins that interact specifically with defined receptor domains and elucidate their role in regulating endocytosis of opioid receptors in several cell types. These studies have direct relevance to mechanisms underlying opiate drug action and addiction. In addition, they may be relevant to understanding alternate mechanisms regulating endocytosis of other G protein-coupled receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012864-02
Application #
6378960
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Koustova, Elena
Project Start
2000-09-28
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$258,125
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
Siljee, Jacqueline E; Wang, Yi; Bernard, Adelaide A et al. (2018) Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nat Genet 50:180-185
Eichel, Kelsie; Jullié, Damien; Barsi-Rhyne, Benjamin et al. (2018) Catalytic activation of ?-arrestin by GPCRs. Nature 557:381-386
Eichel, Kelsie; von Zastrow, Mark (2018) Subcellular Organization of GPCR Signaling. Trends Pharmacol Sci 39:200-208
Kim, Min Woo; Wang, Wenjing; Sanchez, Mateo I et al. (2017) Time-gated detection of protein-protein interactions with transcriptional readout. Elife 6:
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
O'Hayre, Morgan; Eichel, Kelsie; Avino, Silvia et al. (2017) Genetic evidence that ?-arrestins are dispensable for the initiation of ?2-adrenergic receptor signaling to ERK. Sci Signal 10:
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

Showing the most recent 10 out of 54 publications