Deconvolution of Complex GPCR Signaling Pathways

To achieve a comprehensive understanding of the intricate signal transduction mechanisms mediated by the more than 800 GPCRs and their interactions with over 960 distinct trimeric G protein combinations, innovative and systematic approaches are essential. These approaches must enable the direct quantification of enzymatic activities and protein-protein interactions in living cells. Our research employs a cutting-edge single-platform assay uniquely designed to measure the enzymatic activity of GPCRs across a wide range of G protein families in living cells. This assay provides unparalleled quantitative biochemical parameters, facilitating the precise characterization of signaling molecules and enabling a deeper understanding of drug actions targeting 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

Unraveling the molecular and cellular foundations of diseases is essential for designing precise and effective treatments. Recent exome sequencing studies have uncovered mutations in GPCRs, G proteins, effectors, and RGS proteins across a wide spectrum of diseases. Despite these discoveries, the functional impact of many such mutations remains poorly understood.

To address this gap, we conduct comprehensive functional analyses aimed at elucidating the mechanisms underlying disease pathogenesis. By exploring the intricate relationships between the structure and function of key signaling molecules, our studies offer critical insights into the molecular basis of these conditions. More importantly, this research holds the potential to uncover novel therapeutic strategies, paving the way for the treatment of 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?

GPCRs are the linchpins of cellular communication and the focus of countless therapeutic strategies, yet the precise mechanisms by which drugs influence GPCR signaling remain an enigma. Unlocking this knowledge holds the key to designing safer, more effective medications with fewer side effects. Our research delves into the heart of GPCR signaling, exploring how synthetic drugs and physiological agonists orchestrate complex cellular responses. By shedding light on these processes, we aim to revolutionize the development of next-generation therapeutics that harness the full potential of GPCRs.

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)

Transforming Drug Discovery and Design Through GPCR Structural Insights

With their extracellular ligand-binding sites, GPCRs stand as one of the most significant and versatile drug targets in modern medicine. By uncovering the detailed structures of ligand-bound GPCRs and unraveling their functional mechanisms, our research seeks to revolutionize drug discovery. Rather than relying on traditional random screening methods, we strive to pave the way for a more rational, design-driven approach to developing next-generation therapeutics.

Selected References:

  1. The structure and function of the ghrelin receptor coding for drug actions.
    Shiimural Y*, Im D, Tany R, Asada H, Kise R, Kurumiya E, Wakasugi-Masuho H, Yasuda S, Matsui K, Kishikawa J, Kato T, Murata T, Kojima M, Iwata S* and Masuho I*
    Nature Structural & Molecular Biology (2025)
    *Corresponding authors