Src‐dependent phosphorylation of μ‐opioid receptor at Tyr336 modulates opiate withdrawal

Autor: Ping-Yee Law, Horace H. Loh, Lei Zhang, Jing-Gen Liu, Chi Xu, Cherkaouia Kibaly, Patrick W. McGarrah, Yu-Jun Wang, Kyu Young Song
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Narcotic Antagonists
Receptors
Opioid
mu
Pharmacology
Proto-Oncogene Proteins c-fyn
Mice
0302 clinical medicine
Opioid receptor
Phosphorylation
RNA
Small Interfering
Receptor
naloxone‐precipitated opiate withdrawal
Research Articles
Mice
Knockout
Behavior
Animal
Morphine
Chemistry
Naloxone
src-Family Kinases
Molecular Medicine
RNA Interference
Opiate
Locomotion
Proto-oncogene tyrosine-protein kinase Src
Research Article
medicine.medical_specialty
medicine.drug_class
03 medical and health sciences
FYN
Internal medicine
mental disorders
medicine
Animals
Humans
Src‐mediated phosphorylation of MOR at Tyr336
Benzodioxoles
Protein kinase A
opiate addiction
locus coeruleus
Body Weight
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
HEK293 Cells
nervous system
Quinazolines
Locus coeruleus
Tyrosine
lentivirus injection
030217 neurology & neurosurgery
Neuroscience
Zdroj: EMBO Molecular Medicine
ISSN: 1757-4684
1757-4676
Popis: Opiate withdrawal/negative reinforcement has been implicated as one of the mechanisms for the progression from impulsive to compulsive drug use. Increase in the intracellular cAMP level and protein kinase A (PKA) activities within the neurocircuitry of addiction has been a leading hypothesis for opiate addiction. This increase requires the phosphorylation of μ‐opioid receptor (MOR) at Tyr 336 by Src after prolonged opiate treatment in vitro . Here, we report that the Src‐mediated MOR phosphorylation at Tyr 336 is a prerequisite for opiate withdrawal in mice. We observed the recruitment of Src in the vicinity of MOR and an increase in phosphorylated Tyr 336 (pY336) levels during naloxone‐precipitated withdrawal. The intracerebroventricular or stereotaxic injection of a Src inhibitor (AZD0530), or Src shRNA viruses attenuated pY336 levels, and several somatic withdrawal signs. This was also observed in Fyn −/− mice. The stereotaxic injection of wild‐type MOR, but not mutant (Y336F) MOR, lentiviruses into the locus coeruleus of MOR −/− mice restored somatic withdrawal jumping. Regulating pY336 levels during withdrawal might be a future target for drug development to prevent opiate addictive behaviors.
Databáze: OpenAIRE
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