Review
Pharmacology & Pharmacy
Kinjal Patel, Nicola J. Smith
Summary: Primary cilia are important for sensing environmental changes in mammalian cells through the Sonic Hedgehog pathway. GPR161 is a significant player in primary cilia and its unique features may affect receptor function and cAMP compartmentalisation. The recent potential pairing of GPR161 and spexin-1 requires further investigation before GPR161 is considered 'deorphanised'. The constitutive activity and unconventional regulation of GPR161 suggest that it may not require an endogenous ligand.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Developmental Biology
Farah Saad, David R. Hipfner
Summary: The Hedgehog (Hh) pathway is regulated by G protein-coupled receptors (GPCRs) in Drosophila, with Mthl5 identified as a modulator of this pathway. This suggests potential crosstalk between GPCRs and the Hh pathway in mammals as well.
Article
Biology
Marina Goncalves Antunes, Matthieu Sanial, Vincent Contremoulins, Sandra Carvalho, Anne Plessis, Isabelle Becam
Summary: This study reveals how the hedgehog (HH) morphogen regulates the subcellular localization and activity of the oncogenic G-protein-coupled receptor (GPCR) Smoothened (SMO), thereby affecting the morphogenesis of epithelial structures. The authors provide evidence that HH promotes the recycling of internalized SMO, leading to its stabilization. This effect relies on the action of protein kinase A, casein kinase I, and Fused (FU) kinase. Additionally, at high HH levels, FU leads to the local enrichment of SMO in the basal domain of the cell membrane.
Article
Biochemistry & Molecular Biology
Zhiyan Jiang, Liwen Qu, Gaofeng Cui, Guohua Zhong
Summary: Hh pathway antagonist sonidegib was found to have significant effects on the development of Drosophila larvae, causing epidermal abnormalities and decreased motility. Transcriptome analysis revealed its impact on chitin-based cuticle development. These findings shed new light on the potential use of Hh antagonists in agricultural pest management.
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
(2023)
Review
Cell Biology
Haoran Jiang, Daniella Galtes, Jialu Wang, Howard A. Rockman
Summary: This review explores the signaling pathways, dynamic structures, and physiological relevance of the three most important GPCR signaling effectors in the cardiovascular system: heterotrimeric G proteins, GPCR kinases (GRKs), and 8-arrestins. It summarizes their prominent roles in GPCR pharmacology before transitioning into less well-explored areas. The application of new technologies has contributed to an increasing understanding of GPCR structure and downstream effectors.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Review
Immunology
Nan Li, Shan Shan, Xiu-Qin Li, Ting-Ting Chen, Meng Qi, Sheng-Nan Zhang, Zi-Ying Wang, Ling-Ling Zhang, Wei Wei, Wu-Yi Sun
Summary: G protein-coupled receptor kinase 2 (GRK2) plays important roles in regulating signaling pathways associated with fibrotic diseases. Recent research suggests that GRK2 could be a potential therapeutic target for fibrotic diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Clinical Neurology
Serena Galosi, Luca Pollini, Maria Novelli, Katerina Bernardi, Martina Di Rocco, Simone Martinelli, Vincenzo Leuzzi
Summary: In recent years, there has been an increasing number of genetic diseases associated with epilepsy and movement disorders. This study focuses on genetic disorders affecting the G-protein-coupled receptor-cAMP signaling pathway, which result in distinctive clinical phenotypes including movement disorders and epilepsy. Understanding these rare disorders can have important implications for diagnostic suspicion and early detection, as well as for developing targeted treatments.
FRONTIERS IN NEUROLOGY
(2022)
Article
Cell Biology
Yuqing Wang, Shanshan Lu, Yifei Chen, Liang Li, Xia Li, Zhongwei Qu, Junbo Huang, Liu Fan, Chao Yuan, Nan Song, Jun Zhang, Wendong Xu, Shenglian Yang, Yizheng Wang
Summary: The study demonstrated that the SHH-SMO-GLT-1 pathway can control extracellular glutamate and reduce ischemic brain damage by inhibiting SMO. It was found that under ischemic conditions, regulating the SHH-SMO-GLT-1 pathway can decrease the release of extracellular glutamate, thereby protecting neurons.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Yasemin Ozgur-Gunes, Catherine Le Stunff, Malha Chedik, Marie-Pierre Belot, Pierre-Hadrien Becker, Veronique Blouin, Pierre Bougneres
Summary: The gene therapy with hPRKAR1A improved skeletal growth and kidney dysfunction in acrodysostosis, but did not significantly affect the bone length of limbs.
Article
Chemistry, Physical
Shweta Kumari, Abhijit Mitra, Gopalakrishnan Bulusu
Summary: This study investigated the impact of cholesterol binding on the structure and dynamics of the SMO receptor using molecular dynamics simulations. The results revealed that cholesterol had different effects on the conformational dynamics of SMO in the cysteine-rich domain and the transmembrane domain. The study also provided insights into the molecular interactions between cholesterol and SMO.
JOURNAL OF PHYSICAL CHEMISTRY B
(2023)
Review
Biochemistry & Molecular Biology
Jian Yi Chai, Vaisnevee Sugumar, Mohammed Abdullah Alshawsh, Won Fen Wong, Aditya Arya, Pei Pei Chong, Chung Yeng Looi
Summary: The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved in mammals and plays crucial roles in cancer initiation and progression. GLI transcription factors are regulated by both SMO-dependent and SMO-independent mechanisms, with dysregulation leading to tumorigenesis in various cancers. Understanding the complex interplay between GLI and signaling elements could inspire new therapeutic breakthroughs for Hh-GLI-dependent cancers.
Review
Biology
Terry W. Moody, Irene Ramos-Alvarez, Robert T. Jensen
Summary: Cancer growth is regulated by receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs). Different mutations in EGFR and NTSR1 can lead to abnormal cancer proliferation. The use of tyrosine kinase inhibitors and SR48692 as antagonists can impair the transactivation process and inhibit cancer growth.
Article
Multidisciplinary Sciences
Maike Stegen, Andrea Engler, Crista Ochsenfarth, Iris Manthey, Jurgen Peters, Winfried Siffert, Ulrich H. Frey
Summary: The study characterized the human GRK6 promoter and found that the CREB binding site influenced promoter activity. Stimulation with a PKC activator led to decreased GRK6 expression at mRNA and protein levels, suggesting PKC might play a role in regulating GRK6 expression.
Review
Biochemistry & Molecular Biology
Duangnapa Kovanich, Teck Yew Low, Manuela Zaccolo
Summary: cAMP is a second messenger that plays a crucial role in regulating cellular functions. The compartmentalization of cAMP signaling is essential for its specificity, and the formation of dynamic signaling domains is responsible for precise spatiotemporal regulation. Proteomics can be used to identify the components of these domains and define the dynamic landscape of cellular cAMP signaling. Understanding compartmentalized cAMP signaling in physiological and pathological conditions can provide insights into disease mechanisms and guide the development of precision medicine interventions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
John T. Happ, Corvin D. Arveseth, Jessica Bruystens, Daniela Bertinetti, Isaac B. Nelson, Cristina Olivieri, Jingyi Zhang, Danielle S. Hedeen, Ju-Fen Zhu, Jacob L. Capener, Jan W. Brockel, Lily Vu, C. C. King, Victor L. Ruiz-Perez, Xuecai Ge, Gianluigi Veglia, Friedrich W. Herberg, Susan S. Taylor, Benjamin R. Myers
Summary: This study reveals that SMO uses a pseudosubstrate sequence to block the active site of PKA, extinguishing its enzymatic activity and releasing GLI for signal transduction. The interference with SMO-PKA interactions prevents Hh signal transduction.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)