Lei Zhang
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Lei Zhang has a total of 8 co-authors. Here are the top co-authors by number of shared publications:
- Cherkaouia Kibaly
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA
1 shared publication - Chi Xu
Department of Neurobiology and Acupuncture Research, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310053, China
1 shared publication Horace H Loh
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA
1 shared publication- Jing-Gen Liu
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
1 shared publication - Kyu Young Song
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
1 shared publication - Patrick Walsh McGarrah
Division of Hematology and Oncology Mayo Clinic in Rochester Rochester Minnesota USA
1 shared publication
Latest Publications
- Open Access
- 18 August 2017
- Published by Springer Nature in EMBO Molecular Medicine
- Vol. 9 (11) , 1521-1536
Src‐dependent phosphorylation of μ‐opioid receptor at Tyr336 modulates opiate withdrawal
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 Tyr336 by Src after prolonged opiate treatment in vitro. Here, we report that the Src‐mediated MOR phosphorylation at Tyr336 is a prerequisite for opiate withdrawal in mice. We observed the recruitment of Src in the vicinity of MOR and an increase in phosphorylated Tyr336 (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. Synopsis The μ‐opioid receptor (MOR) non‐canonical signaling pathway involves its phosphorylation at Tyr336 by Src kinase within the MOR signal complex. The focal event of MORY336 phosphorylation may be the key for adenylyl cyclase superactivation during the withdrawal/negative stage of opiate addiction. The phosphorylation levels of MORY336 and SrcY416 increased during naloxone‐precipitated withdrawal in wild‐type mice. The intracerebroventricular or stereotaxic injection of a Src inhibitor (AZD0530), or Src shRNA viruses reduced pMORY336 and pSrcY416 levels, and several somatic withdrawal signs. Increases of pMORY336 levels as well as some somatic withdrawal signs after naloxone‐precipitated withdrawal were not observed in Fyn−/− mice. The stereotaxic injection of wild‐type MOR lentiviruses into the locus coeruleus of MOR−/− mice restored somatic withdrawal jumping and wet dog shaking. The stereotaxic injection of the phosphorylation‐deficient mutant (Y336F) MOR, in which the mutation of Tyr336 to Phe blocks Src‐mediated phosphorylation, attenuated naloxone‐precipitated withdrawal.
- 18 August 2017
- Published by Springer Nature in EMBO Molecular Medicine
- Vol. 9 (11) , 1521-1536
Open AccessSrc‐dependent phosphorylation of μ‐opioid receptor at Tyr336 modulates opiate withdrawal
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 Tyr336 by Src after prolonged opiate treatment in vitro. Here, we report that the Src‐mediated MOR phosphorylation at Tyr336 is a prerequisite for opiate withdrawal in mice. We observed the recruitment of Src in the vicinity of MOR and an increase in phosphorylated Tyr336 (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. Synopsis The μ‐opioid receptor (MOR) non‐canonical signaling pathway involves its phosphorylation at Tyr336 by Src kinase within the MOR signal complex. The focal event of MORY336 phosphorylation may be the key for adenylyl cyclase superactivation during the withdrawal/negative stage of opiate addiction. The phosphorylation levels of MORY336 and SrcY416 increased during naloxone‐precipitated withdrawal in wild‐type mice. The intracerebroventricular or stereotaxic injection of a Src inhibitor (AZD0530), or Src shRNA viruses reduced pMORY336 and pSrcY416 levels, and several somatic withdrawal signs. Increases of pMORY336 levels as well as some somatic withdrawal signs after naloxone‐precipitated withdrawal were not observed in Fyn−/− mice. The stereotaxic injection of wild‐type MOR lentiviruses into the locus coeruleus of MOR−/− mice restored somatic withdrawal jumping and wet dog shaking. The stereotaxic injection of the phosphorylation‐deficient mutant (Y336F) MOR, in which the mutation of Tyr336 to Phe blocks Src‐mediated phosphorylation, attenuated naloxone‐precipitated withdrawal.