Deconvolution of complex GPCR signaling pathways

For a deep understanding of complex GPCR signal transduction consisting of more than 800 GPCRs and 960 different combinations of trimeric G proteins, comprehensive and systematic approaches that directly quantitate enzymatic activities and protein-protein interactions in living cells are required. We have employed a unique single platform assay capable of measuring GPCR's enzymatic activity across most G proteins in living cells. This assay has a superior capability to obtain quantitative biochemical parameters, allowing precise characterization of signaling molecules and drug action on GPCRs.

Selected References:

  1. Rules and mechanisms governing G protein coupling selectivity of GPCRs.
    Masuho I*, Kise R, Gainza P, Moo EV, Li X, Tany R, Wakasugi-Masuho H, Correia BE, and Martemyanov KA*.
    Cell Reports (2023)
    *Co-corresponding authors

  2. Diversity of the Gβγ complexes defines spatial and temporal bias of GPCR signaling.
    Masuho I, Skamangas NK, Muntean BS, Martemyanov KA.
    Cell Systems (2021)
    *Co-corresponding authors

  3. A global map of G protein signaling regulation by RGS proteins.
    Masuho I, Balaji S, BMuntean BS, Skamangas NK, Chavali S, Tesmer JJG, Babu MM, Martemyanov KA.
    Cell (2020)

  4. Dopamine receptor DAMB signals via Gq to mediate forgetting in Drosophila.
    Himmelreich S*, Masuho I*, Berry JA, MacMullen C, Skamangas NK, Martemyanov KA, Davis RL.
    Cell Reports (2017)
    * These authors contributed equally to this work

  5. Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors.
    Masuho I, Ostrovskaya O, Kramer GM, Jones CD, Xie K, Martemyanov KA.
    Sci Signal. (2015)

 

Paving the way for precision medicine targeting GPCR signaling

Understanding the molecular and cellular basis of diseases is for designing appropriate and effective treatments. Recent exome studies identified mutations in GPCRs, G proteins, effectors, and RGS proteins from a wide range of diseases. However, the effects of such mutations on the function of these important signaling molecules are not clear in most cases. Therefore, we perform functional studies, which will be instrumental in dissecting the mechanisms of disease pathogenesis and defining the relationships between the structure and function of signaling molecules. More significantly, this study has the possibility to find therapeutic means to treat a broad range of diseases.

Selected References:

  1. Gαo is a major determinant of cAMP signaling in the pathophysiology of movement disorders.
    Muntean BS, Masuho I, Dao M, Sutton LP, Zucca S, Iwamoto H, Patil DN, Wang D, Birnbaumer L, Blakely RD, Grill B, Martemyanov KA.
    Cell Reports (2021)

  2. Molecular deconvolution platform to establish disease mechanisms by surveying GPCR signaling.
    Masuho I, Chavali S, Muntean BS, Skamangas NK, Simonyan K, Patil DN, Kramer GM, Ozelius L, and Babu MM, Martemyanov KA.
    Cell Reports (2018)

  3. Pharmacogenomics of GPCR drug targets.
    Hauser AS, Chavali S, Masuho I, Jahn LJ, Martemyanov KA, Gloriam DE, Babu MM.
    Cell (2018)

  4. Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans.
    Lohmann K*, Masuho I*, Patil DN, Baumann H, Hebert E, Steinrücke S, Trujillano D, Skamangas NK, Dobricic V, Hüning I, Gillessen-Kaesbach G, Westenberger A, Savic-Pavicevic D, Münchau A, Oprea G, Klein C, Rolfs A, Martemyanov KA.
    Human Molecular Genetics (2017)
    *These authors contributed equally to this work

  5. GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.
    Shamseldin HE*, Masuho I*, Anazi A, Yamani S, Patil DN, Martemyanov KA, Alkuraya FS.
    Genome Biology (2016)
    *These authors contributed equally to this work

  6. Mutations in GNAL cause primary torsion dystonia.
    Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, Factor S, Lang AE, Liang TW, Trosch RM, White S, Ainehsazan E, Hervé D, Sharma N, Ehrlich ME, Martemyanov KA, Bressman SB, Ozelius LJ.
    Nature Genetics (2013)

How do synthetic drugs control GPCR signaling?

Despite the tractability of GPCRs as drug targets, there are substantial challenges in understanding drug action mechanisms at these receptors. A precise understanding of the molecular mechanism of GPCR signaling would facilitate the development of more effective and less toxic drugs. Thus, we investigate the nature of signaling molecules in GPCR signal transduction elicited by physiological agonists and synthetic drugs.

Selected References:

  1. Ligand-directed bias of G protein signaling at the dopamine D2 receptor.
    Moo EV, Harpsøe K, Hauser AS, Masuho I, Bräuner-Osborne H, Gloriam DE, Martemyanov KA.
    Cell Chemical Biology (2021)

  2. Pharmacogenomics of GPCR drug targets.
    Hauser AS, Chavali S, Masuho I, Jahn LJ, Martemyanov KA, Gloriam DE, Babu MM.
    Cell (2018)

  3. Synergistically acting agonists and antagonists of G protein–coupled receptors prevent photoreceptor cell degeneration.
    Chen Y, PalczewskaG, Masuho I, Gao S, Jin H, Dong Z, Gieser L, Brooks MJ, Kiser PD, Kern TS, Martemyanov KA, Swaroop A, Palczewski K.
    Sci Signal. (2016)

  4. Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors.
    Masuho I, Ostrovskaya O, Kramer GM, Jones CD, Xie K, Martemyanov KA.
    Sci Signal. (2015)