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    Hong-Sheng Li PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentNeurobiology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-6702
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative

        Academic Background

        B.Sc. with high honors in Biochemistry,
        Wuhan University, China
        1991
        Ph.D., Shanghai Brain Research Institute,
        Chinese Academy of Science, China
        1996
        Postdoctoral Fellow, Johns Hopkins University 1996-2001
        The Albert L. Lehninger Postdoctoral Fellow Award, Johns Hopkins University 2001

        Neuronal regulation of membrane receptor signaling

        Photo: Hong-Sheng 







Li, Ph.D.Our lab is interested in neuronal signaling events triggered by membrane receptors and the regulation mechanisms of receptor signaling. Our current researches are focused on a G-protein coupled receptor (GPCR): the fly light receptor rhodopsin.

        GPCRs are the largest family of receptors on the cell membrane. They mediate transmembrane signaling of numerous neurotransmitters, hormones, cytokines and sensory stimuli. Through heterotrimeric G proteins and downstream second messengers such as IP3/Ca2+ and cAMP, GPCRs alter cell membrane potential, control neuronal secretion and regulate cell proliferation and degeneration. To fine-tune the signaling and prevent excitotoxicity-mediated neuronal damage or degeneration, the cells control the GPCR activitythrough variousregulatory molecules including arrestins and GPCR kinases. The phosphorylation and binding to arrestin uncouple GPCR from the G protein, a process termed deactivation or desensitization of receptor. In addition, prolonged activation of GPCR causes endocytosis and downregulation of the receptor protein, and leads to long-term desensitization of the cell to extracellular stimuli.

        Most investigations on the regulation of GPCR were carried out in cultured cells; however, using fly rhodopsin as a genetic model, we are identifying in vivo mechanisms of GPCR regulation in intact photoreceptor neurons. Upon light stimulation, rhodopsin activates a Gq protein to stimulate phospholipase C, which opens TRP family Ca2+/cation channels to depolarize the photoreceptor neuron. To ensure rapid termination of visual response at the end of stimulation, rhodopsin needs to be deactivated promptly after activating a Gq molecule. A visual arrestin Arr2 plays a pivotal role in the deactivation of rhodopsin. Recently we have revealed another pathway of rhodopsin regulation: a fly calmodulin-binding transcription activator (dCAMTA) promotes expression of an F-box and leucine-rich repeat protein dFbxl4 to potentiate deactivation of rhodopsin. Interestingly,in addition to terminating the light response, the Arr2- and dCAMTA/dFbxl4-mediated rhodopsin deactivations arerequiredto maintain thephotoreceptor sensitivity throughcontrollinga Gq-mediated rhodopsin endocytic pathway.

        Using a combination of molecular and cell biological, electrophysiological and genetic approaches, we are currently isolating and characterizing additional fly mutants that are defective in the control of rhodopsin activity and/or endocytosis. Some isolated mutantshave slow dynamics of visual transduction, while some othersundergo severe retinal degeneration due to abnormal rhodopsin signaling.We have identified the affectedgenes in severalmutants, and found they all have mammalian homologs highly expressed in the brain.

        Figure

        Figure



        Rotation Projects

        Rotation projects

        Rotation students in the lab will have the following choices of research projects:

        1) Further characterize the dCAMTA/dFbxl4-mediate deactivation of rhodopsin and the morphological defects due to loss of this pathway.

        2) Participate in the characterization of additional mutant flies that have defective rhodopsin regulation, and investigate why abnormal rhodopsin signaling leads to retinal degeneration.

        3) Explore the functions of rhodopsin regulatory molecules in other receptor signaling cascades.

        4) Isolate new fly mutants with impaired GPCR signaling.



        Post Docs

        A postdoctoral position is available to study in this laboratory. Contact Dr. Li for additional details.

        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Luan Z, Li HS. Inwardly rectifying potassium channels in Drosophila. Sheng Li Xue Bao. 2012 Oct 25; 64(5):515-9.
          View in: PubMed
        2. Hu W, Wan D, Yu X, Cao J, Guo P, Li HS, Han J. Protein Gq modulates termination of phototransduction and prevents retinal degeneration. J Biol Chem. 2012 Apr 20; 287(17):13911-8.
          View in: PubMed
        3. Cao J, Li Y, Xia W, Reddig K, Hu W, Xie W, Li HS, Han J. A Drosophila metallophosphoesterase mediates deglycosylation of rhodopsin. EMBO J. 2011 Sep 14; 30(18):3701-13.
          View in: PubMed
        4. Venkatachalam K, Wasserman D, Wang X, Li R, Mills E, Elsaesser R, Li HS, Montell C. Dependence on a retinophilin/myosin complex for stability of PKC and INAD and termination of phototransduction. J Neurosci. 2010 Aug 25; 30(34):11337-45.
          View in: PubMed
        5. Ni L, Guo P, Reddig K, Mitra M, Li HS. Mutation of a TADR protein leads to rhodopsin and Gq-dependent retinal degeneration in Drosophila. J Neurosci. 2008 Dec 10; 28(50):13478-87.
          View in: PubMed
        6. Han J, Reddig K, Li HS. Prolonged G(q) activity triggers fly rhodopsin endocytosis and degradation, and reduces photoreceptor sensitivity. EMBO J. 2007 Dec 12; 26(24):4966-73.
          View in: PubMed
        7. Gong P, Han J, Reddig K, Li HS. A potential dimerization region of dCAMTA is critical for termination of fly visual response. J Biol Chem. 2007 Jul 20; 282(29):21253-8.
          View in: PubMed
        8. Han J, Gong P, Reddig K, Mitra M, Guo P, Li HS. The fly CAMTA transcription factor potentiates deactivation of rhodopsin, a G protein-coupled light receptor. Cell. 2006 Nov 17; 127(4):847-58.
          View in: PubMed
        9. Xu H, Lee SJ, Suzuki E, Dugan KD, Stoddard A, Li HS, Chodosh LA, Montell C. A lysosomal tetraspanin associated with retinal degeneration identified via a genome-wide screen. EMBO J. 2004 Feb 25; 23(4):811-22.
          View in: PubMed
        10. Ma HT, Venkatachalam K, Li HS, Montell C, Kurosaki T, Patterson RL, Gill DL. Assessment of the role of the inositol 1,4,5-trisphosphate receptor in the activation of transient receptor potential channels and store-operated Ca2+ entry channels. J Biol Chem. 2001 Jun 1; 276(22):18888-96.
          View in: PubMed
        11. Li HS, Montell C. TRP and the PDZ protein, INAD, form the core complex required for retention of the signalplex in Drosophila photoreceptor cells. J Cell Biol. 2000 Sep 18; 150(6):1411-22.
          View in: PubMed
        12. Li HS, Xu XZ, Montell C. Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron. 1999 Sep; 24(1):261-73.
          View in: PubMed
        13. Wes PD, Xu XZ, Li HS, Chien F, Doberstein SK, Montell C. Termination of phototransduction requires binding of the NINAC myosin III and the PDZ protein INAD. Nat Neurosci. 1999 May; 2(5):447-53.
          View in: PubMed
        14. Li HS, Porter JA, Montell C. Requirement for the NINAC kinase/myosin for stable termination of the visual cascade. J Neurosci. 1998 Dec 1; 18(23):9601-6.
          View in: PubMed
        15. Xu XZ, Wes PD, Chen H, Li HS, Yu M, Morgan S, Liu Y, Montell C. Retinal targets for calmodulin include proteins implicated in synaptic transmission. J Biol Chem. 1998 Nov 20; 273(47):31297-307.
          View in: PubMed
        16. Li HS, Zhao ZQ. Small sensory neurons in the rat dorsal root ganglia express functional NK-1 tachykinin receptor. Eur J Neurosci. 1998 Apr; 10(4):1292-9.
          View in: PubMed
        17. Xu XZ, Li HS, Guggino WB, Montell C. Coassembly of TRP and TRPL produces a distinct store-operated conductance. Cell. 1997 Jun 27; 89(7):1155-64.
          View in: PubMed
        18. Li HS, Zhao ZQ. [Progress in the study of the molecular neurobiology of substance P]. Sheng Li Ke Xue Jin Zhan. 1994 Jan; 25(1):37-41.
          View in: PubMed
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