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G protein-coupled receptors (GPCRs) and their downstream signaling pathways are critical targets for current pharmacotherapy [...].
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http://dx.doi.org/10.3390/ijms25010291 | DOI Listing |
Handb Exp Pharmacol
September 2025
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Research conducted over the last 15 years indicates that cAMP is generated not just from the plasma membrane but also from intracellular compartments, particularly in endosomes, where receptors are redistributed during the endocytosis process. This review centers on the parathyroid hormone type 1 receptor (PTHR) as a model for a peptide hormone GPCRs that generates cAMP from various locations with distinct duration and pharmacological effectiveness. We discuss how structural dynamics simulations aid in designing ligands that induce cAMP location bias, ultimately answering how the spatiotemporal generation of cAMP affects pharmacological responses mediated by the PTHR.
View Article and Find Full Text PDFHandb Exp Pharmacol
September 2025
National Institute of Biological Sciences, Beijing, China.
G protein-coupled receptors (GPCRs) engage multiple transducers to regulate distinct physiological processes. These transducers include various G proteins subtypes, GPCR kinases (GRKs), and β-arrestins. In addition to promoting receptor desensitization, β-arrestins serve as scaffolds for signaling via non-G protein pathways.
View Article and Find Full Text PDFHandb Exp Pharmacol
September 2025
Department of Medicine, Duke University Medical Center, Durham, NC, USA.
GPCRs are known for their versatile signaling roles at the plasma membrane; however, recent studies have revealed that these receptors also function within various intracellular compartments, such as endosomes, the Golgi apparatus, and the endoplasmic reticulum. This spatially distinct signaling, termed location bias, allows GPCRs to initiate unique signaling cascades and influence cellular processes-including cAMP production, calcium mobilization, and protein phosphorylation-in a compartment-specific manner. By mapping the impact of GPCR signaling from these subcellular locations, this chapter emphasizes the mechanisms underlying signaling from intracellular receptor pools in diversifying receptor functionality.
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September 2025
Tsinghua University, Beijing, China.
The μ-opioid receptor (μOR) is the primary drug target of opioid analgesics such as morphine and fentanyl. Activation of μORs in the central nervous system inhibits ascending pain signaling to the cortex, thereby producing analgesic effects. However, the clinical use of opioid analgesics is severely limited by adverse side effects, including respiratory depression, constipation, addiction, and the development of tolerance.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Cell Biol Lipids
September 2025
Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, V8W 2Y2, Canada; University of Victoria Genome BC Proteomics Centre, Vi
The class I phosphoinositide 3-kinase pathway (PI3K) is a master regulator of cellular growth, and plays essential roles in controlling immune cell function, metabolism, chemotaxis and proliferation. Activation of class I PI3Ks generates the signalling lipid PIP that activates multiple pro-growth signalling pathways. Class I PI3Ks can be activated by multiple plasma membrane stimuli, including G-protein coupled receptors, Ras superfamily GTPases, and receptor tyrosine kinases.
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