Opioid and catecholamine receptors are key regulators of neurophysiology and behavior, and are important targets of therapeutic and abused drugs. These receptors are fundamentally regulated by endocytosis and specific membrane trafficking events in the endocytic pathway. Endocytic membrane trafficking has long been recognized to influence adaptation or maladaptation of the endogenous opioid and catecholamine systems to chronic or repeated drug administration. It is now evident that endocytic trafficking of receptors also impacts the acute response and may thereby differentiate the actions of therapeutically and addiction - relevant drugs over a wide time frame. In the previous funding period we defined much of the biochemical machinery determining the endocytic regulation of opioid receptors, and established effects on both long-term and acute signaling. The proposed studies build on progress made in the previous funding period to elucidate a fundamentally new mechanism of opioid and adrenergic receptor signaling based on receptor activation in internal membrane compartments as well as the plasma membrane. We propose to (1) Define mechanisms that limit GPCR signal strength or duration from endosomes; (2) Determine how endocytosis facilitates downstream transcriptional control by GPCRs; and (3) Delineate membrane trafficking properties of opioid receptors in axons.

Public Health Relevance

Addictive opiate drugs such as morphine and heroin activate the same cellular receptors as endogenous opioid neuropeptides, yet produce pathological effects after prolonged or repeated administration. We seek to understand the underlying cell biology and biochemistry of these drug effects that might be useful reveal new therapeutic targets for treating opiate tolerance and addictive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010711-24
Application #
9858316
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Wu, Da-Yu
Project Start
1997-01-15
Project End
2023-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
24
Fiscal Year
2020
Total Cost
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
94118
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