Review
Biochemistry & Molecular Biology
Dinesh Kankanamge, Mithila Tennakoon, Ajith Karunarathne, N. Gautam
Summary: This review focuses on the current knowledge about the potential roles and mechanisms of the gamma subunits of heterotrimeric G proteins. Loss or dysregulation of specific gamma subunit types can result in different phenotypes and even cancers. Imaging studies have revealed that the membrane affinity of gamma subunits controls the sensitivity and adaptation of cells to external signals.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Jun Xu, Nobuo Koizumi, Yusuke V. Morimoto, Ryo Ozuru, Toshiyuki Masuzawa, Shuichi Nakamura
Summary: Nucleotide second messengers play crucial roles in signal transduction in various organisms. A study has found that the swimming motility of the soil bacterium Leptospira kobayashii can be rapidly modulated by light stimulation. Through analysis of a loss-of-photoresponsivity mutant, a novel sensory gene was identified, and the light-dependent synthesis of cyclic adenosine monophosphate (cAMP) was elucidated. These findings reveal a new role for cAMP in controlling the flagella-dependent motility of Leptospira and highlight the global distribution of the newly discovered photoactivated cyclase among diverse microbial species.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Yukiko Sato, Dusik Kim, Mark J. Turner, Yishan Luo, Syeda Sadaf Zehra Zaidi, David Y. Thomas, John W. Hanrahan
Summary: CFTR is a tightly regulated anion channel that mediates chloride and bicarbonate conductance. This study found that the regulation of CFTR depends on the cell type, and identified FOXI1 as a regulator of ionocyte markers and CFTR expression. The study also revealed that PDE1C can suppress CFTR activity. These findings have implications for the development of therapeutics for cystic fibrosis.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2023)
Article
Behavioral Sciences
Zhong Ding, Gregory T. Knipp, Richard M. van Rijn, Julia A. Chester, Val J. Watts
Summary: Heterologous sensitization of adenylyl cyclase is enhanced cAMP response following G alpha(i/o)-coupled receptors activation, which can be abolished by pharmacological inhibition of Cullin3 with MLN4924. MLN4924 was found to reduce alcohol-induced locomotor sensitization and allodynia in an inflammatory pain model, potentially through blocking AC sensitization. These findings suggest a new pathway for drug development for disorders associated with AC sensitization.
BEHAVIOURAL BRAIN RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Shizhong A. Dai, Qi Hu, Rong Gao, Emily E. Blythe, Kouki K. Touhara, Hayden Peacock, Ziyang Zhang, Mark von Zastrow, Hiroaki Suga, Kevan M. Shokat
Summary: This article explores a chemical library of 1012 cyclic peptides and identifies two macrocyclic peptides, GN13 and GD20, that can antagonize the activity and inactive states of the key protein Gas in the G protein-coupled receptor cascade. These macrocyclic peptides have high selectivity and specificity and can modulate cellular signaling through binding to crystallographically defined pockets.
Article
Chemistry, Medicinal
Esteban G. Vega Hissi, Antonella B. De Costa Guardamagna, Adriana D. Garro, Cristian R. Falcon, Marko Anderluh, Tihomir Tomasic, Danijel Kikelj, Agustin Yaneff, Carlos A. Davio, Ricardo D. Enriz, Adolfo R. Zurita
Summary: This study reported a derivative of N-(piperidin-4-yl)-1H-pyrrole-2-carboxamide as a new inhibitor for the adenylate cyclase of Giardia lamblia, and developed a model for this specific enzyme. The new inhibitor was found to have a competitive mechanism of action against the enzyme, serving as an excellent starting point for the development of new metabolic inhibitors for G. lamblia.
Article
Multidisciplinary Sciences
Donghoon Ahn, Davide Provasi, Nguyen Minh Duc, Jun Xu, Leslie Salas-Estrada, Aleksandar Spasic, Min Woo Yun, Juyeong Kang, Dongmin Gim, Jaecheol Lee, Yang Du, Marta Filizola, Ka Young Chung
Summary: In this study, a novel Bayesian integrative modeling framework was used to investigate the conformational changes of the beta(2)-adrenergic receptor (β(2)AR)-Gs complex after GDP release and GTP binding. The results showed rapid GTP binding and dissociation of Gas from β(2)AR and G(βγ), and a slow closing of the G(alpha s)α-helical domain. Additionally, the screening identified MAGE D2 as a novel AHD-binding protein that can accelerate the GTP-induced closing of G(alpha s) AHD.
Article
Pharmacology & Pharmacy
Masaki Saito, Ayano Chiba, Takeya Sato, Takahiro Moriya, Jun Sukegawa, Norimichi Nakahata
Summary: Proteins interacting with G protein-coupled receptors can modulate signal transduction, and in this study, Tctex-1 was found to enhance PTHR-mediated signaling by activating adenylyl cyclase. Additionally, Tctex-1 was shown to directly bind to AC type 6, revealing a novel mechanism of GPCR/G(s) signaling regulation by Tctex-1.
JOURNAL OF PHARMACOLOGICAL SCIENCES
(2021)
Article
Biochemical Research Methods
Hidetoshi Urakubo, Sho Yagishita, Haruo Kasai, Yoshiyuki Kubota, Shin Ishii
Summary: In this study, a computational model of D2 signaling was built to determine the conditions for detecting DA dips. It was found that the detection of DA dip requires a delicate balance between D2R and RGS levels, which seem to be crucial for normal learning and memory. Imbalance between D2R and RGS, as seen in patients with schizophrenia and DYT1 dystonia, may disrupt long-term memory formation and lead to associated symptoms.
PLOS COMPUTATIONAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Jong-Chan Park, Alex Luebbers, Maria Dao, Ana Semeano, Anh Minh Nguyen, Maria P. Papakonstantinou, Stefan Broselid, Hideaki Yano, Kirill A. Martemyanov, Mikel Garcia-Marcos
Summary: In this study, researchers uncover a new mechanism of G protein regulation involving the protein GINIP, which biases inhibitory GPCR responses towards Gbg signaling and dampens Gai-GTP signaling. This mechanism is crucial for maintaining balanced neurotransmission and preventing increased seizure susceptibility in mice.
Review
Pharmacology & Pharmacy
David J. Marcus, Michael R. Bruchas
Summary: Despite the fact that G protein-coupled receptors (GPCRs) are targeted by about 40% of FDA-approved drugs, there is still a lack of understanding of their physiological and functional roles at the systems level. Classic pharmacological experiments and in vitro assays have provided insights into GPCR signaling cascades, but the interaction of these cascades across different cell types, tissues, and organ systems remains unclear. The development of optical tools has allowed researchers to investigate GPCR signaling in vivo and in vitro, providing temporal and spatial resolution. These tools have been used to explore the functional roles of different populations of GPCRs and their signaling cascades at the systems level.
PHARMACOLOGICAL REVIEWS
(2023)
Article
Physiology
Thomas Rossetti, Jacob Ferreira, Lubna Ghanem, Hannes Buck, Clemens Steegborn, Robert W. Myers, Peter T. Meinke, Lonny R. Levin, Jochen Buck
Summary: This article describes in vitro assays focused on soluble adenylyl cyclase (sAC) for identification and characterization of inhibitors for therapeutic use. By improving the assays, the affinity and binding kinetics of the inhibitors can be evaluated, enhancing the assessment of in vivo efficacy.
FRONTIERS IN PHYSIOLOGY
(2022)
Article
Genetics & Heredity
Christina M. Campagna, Hayley McMahon, Inna Nechipurenko
Summary: This study reveals the role of RIC-8 protein in cilia membrane morphogenesis in certain nematode sensory neurons. RIC-8 interacts with AGS-3 and ODR-3 to shape cilia morphology through a non-canonical G protein signaling pathway.
Article
Neurosciences
Paramita Basu, Lilian Custodio-Patsey, Pranav Prasoon, Bret N. Smith, Bradley K. Taylor
Summary: The study found that the mechanisms underlying chronic postoperative pain may differ between males and females, with certain signaling pathways in the dorsal horn playing a key role in this process. Sustained signaling of spinal kappa opioid receptors (KOR) can inhibit PKA-dependent mechanisms that drive postoperative LS. These findings support the development of new pharmacotherapy for chronic postoperative pain.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Shuya Kate Huang, Louis-Philippe Picard, Rima S. M. Rahmatullah, Aditya Pandey, Ned Van Eps, Roger K. Sunahara, Oliver P. Ernst, Adnan Sljoka, R. Scott Prosser
Summary: Fluorine nuclear magnetic resonance spectroscopy was used to study the conformational equilibria of the human stimulatory G-protein alpha subunit (G(s)α) in different states. The results showed that the equilibrium is influenced by nucleotide, beta gamma subunit, lipid bilayer, and adenosine A(2A) receptor (A(2A)R). Different helices of G(s)α exhibited dynamic behavior and underwent interactions and transitions associated with G-protein activation. The study revealed a conformational landscape influenced by nucleotides, lipid bilayer, and G-protein-coupled receptor.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)