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G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities, 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 20 July 2026 | Viewed by 462

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Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute City of Hope, Duarte, CA 91010, USA
Interests: G protein-coupled receptor; bone regeneration; mesenchymal stem cells; diabetes; pancreatic beta cell regeneration
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Special Issue Information

Dear Colleagues,

G protein-coupled receptors (GPCRs) are the largest and most diverse family of membrane receptors in eukaryotic cells. These seven-transmembrane domain proteins are activated by a wide range of ligands—e.g., hormones, neurotransmitters, ions, and sensory stimuli—triggering downstream signaling cascades through heterotrimeric G proteins. GPCRs regulate numerous physiological processes such as vision, taste, smell, immune responses, and neurotransmission.

The plethora of processes regulated by GPCRs makes them critical targets for therapeutic intervention. Approximately one-third of all clinically approved drugs act through the modulation of GPCR-mediated signaling. Yet, many aspects of GPCR signaling are still not fully understood, particularly regarding receptor specificity, biased signaling, and the spatiotemporal dynamics of receptor activation and desensitization.

Advances in structural biology, computational modeling, and high-throughput screening have significantly expanded our understanding of GPCR pharmacology, opening new avenues for drug discovery and precision medicine.

This research topic aims to further elucidate the molecular mechanisms governing GPCR activity and their implications in health and disease, emphasizing the role of these receptors in different systems and tissues. A thorough understanding of GPCR-mediated pathways may play a critical role in the development of effective therapeutic approaches.

Dr. Joanna Filipowska
Guest Editor

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Keywords

  • GPCR
  • cell signaling
  • small-molecule drugs
  • biased signaling
  • endosomal signaling
  • post-translational modification
  • GPCR internalization
  • phosphorylation barcode

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Published Papers (1 paper)

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Research

18 pages, 6298 KB  
Article
Molecular Dynamics Insights into TAS1R2 Transmembrane Domain Activation
by Yongcheng Lu, Xinyi Ma, Ziyue Meng and Meng Cui
Int. J. Mol. Sci. 2025, 26(23), 11464; https://doi.org/10.3390/ijms262311464 - 26 Nov 2025
Viewed by 247
Abstract
Sweet taste receptors (STRs) are class C G protein-coupled receptors (GPCRs) that function as heterodimers of TAS1R2 and TAS1R3. These receptors possess multiple binding sites and can be activated by a wide range of sweet-tasting compounds. Interestingly, TAS1R2 alone or even its extracellular [...] Read more.
Sweet taste receptors (STRs) are class C G protein-coupled receptors (GPCRs) that function as heterodimers of TAS1R2 and TAS1R3. These receptors possess multiple binding sites and can be activated by a wide range of sweet-tasting compounds. Interestingly, TAS1R2 alone or even its extracellular domain-truncated form (TAS1R2-TMD), can act as a functional receptor. Previous studies demonstrated that the sweetener S819 and the sweet inhibitor amiloride act through the transmembrane domain (TMD) of TAS1R2; however, the molecular mechanisms underlying these ligand-specific effects remain unclear, largely due to the historical lack of experimentally determined full-length STR structures. Recent breakthroughs in cryo-EM structural determination of the full-length TAS1R2/TAS1R3 complex now offer an unprecedented opportunity to elucidate receptor activation mechanisms at atomic resolution. In this study, we investigated ligand-induced conformational dynamics of hTAS1R2-TMD using microsecond-scale molecular dynamics (MD) simulations on three systems: hTAS1R2-TMD/S819 (agonist-bound), hTAS1R2-TMD/amiloride (antagonist-bound), and hTAS1R2-TMD (apo). Comparative analyses revealed that agonist and antagonist binding distinctly modulate key structural switches, including the conserved ionic lock (E6.35-R3.50), which stabilizes the inactive state and disrupts upon activation. Notably, we identified a novel salt bridge (D7.32-R3.32) that forms preferentially in the active state, potentially serving as a unique molecular switch for TAS1R2. Additional analyses uncovered ligand-specific rearrangements in hydrogen-bonding and hydrophobic interaction networks. These results provide atomistic insights into how agonists and antagonists differentially modulate TAS1R2 activation and lay a structural foundation for designing novel sweeteners and taste modulators. Full article
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