Currently, attention was mainly paid to biased signaling modulators targeting G protein-coupled receptors The biased signaling modulation of non-GPCR receptors has yet to be exploited. receptor 4 (TLR4) is one such non-GPCR receptor, which involves MyD88-dependent and TRIF-dependent signaling Small molecules biasedly modulating the TLR4 signaling axis not only provide probes to fine-tune receptor conformation and signaling but also provide an opportunity to identify promising drug candidates.

7 pass transmembrane domain, Class F GPCR family protein) plays a crucial role in the Hedgehog (HH) signaling In the absence of HH signaling, SMO is inhibited by Patched 1 (PTC1; a 12 pass transmembrane domain protein

August 2022 GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors "Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors." Read more at the source #DrGPCR #GPCR #IndustryNews

However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to Here, we characterize divergent signaling signatures in mouse astrocytes of the PFC and primary sensory Instead, fast calcium signals in PFC astrocytes are time locked to dopamine release and are mediated Thus, we identify astrocytes as active players in dopaminergic signaling in the PFC, contributing to

We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible

October 2022 "Enzymatic and cellular signalling biosensors are used to decipher the activities of complex Here, we briefly summarize a subset of this field with accelerating importance: transducer biosensors selectivity, with an emphasis on sensors measuring receptor association and activation of heterotrimeric signalling

Ca2+ (Ca2+o ) via a dimeric extracellular Venus flytrap (VFT) unit that activates G protein-dependent signaling corresponding to heterozygous familial hypocalciuric hypercalcemia type-1 (FHH-1), supported maximal signaling In contrast, a single WT HH bundle was insufficient for maximal signaling and there was no functional Finally, we observed that the Ca2+o -stimulated CaSR operated exclusively via signaling in-trans and not via combined in-trans and in-cis signaling.

October 2022 Dimerization of β2-adrenergic receptor is responsible for the constitutive activity subjected to inverse agonism "Dimerization of beta 2-adrenergic receptor (β2-AR) has been observed across various physiologies. However, the function of dimeric β2-AR is still elusive. Here, we revealed that dimerization of β2-AR is responsible for the constitutive activity of β2-AR generating inverse agonism. Using a co-immunoimmobilization assay, we found that transient β2-AR dimers exist in a resting state, and the dimer was disrupted by the inverse agonists. A Gαs preferentially interacts with dimeric β2-AR, but not monomeric β2-AR, in a resting state, resulting in the production of a resting cAMP level. The formation of β2-AR dimers requires cholesterol on the plasma membrane. The cholesterol did not interfere with the agonist-induced activation of monomeric β2-AR, unlike the inverse agonists, implying that the cholesterol is a specific factor regulating the dimerization of β2-AR. Our model not only shows the function of dimeric β2-AR but also provides a molecular insight into the mechanism of the inverse agonism of β2-AR." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter

August 2022 "The calcium-permeable cation channel TRPM3 can be activated by heat and the endogenous steroid pregnenolone sulfate. TRPM3's best understood function is its role as a peripheral noxious heat sensor in mice. However, the channel is expressed in various tissues and cell types including neurons as well as glial and epithelial cells. TRPM3 expression patterns differ between species and change during development. Furthermore, a plethora of TRPM3 variants that result from alternative splicing have been identified and the majority of these isoforms are yet to be characterized. Moreover, the mechanisms underlying regulation of TRPM3 are largely unexplored. In addition, a micro-RNA gene (miR-204) is located within the TRPM3 gene. This complexity makes it difficult to obtain a clear picture of TRPM3 characteristics. However, a clear picture is needed to unravel TRPM3's full potential as experimental tool, diagnostic marker and therapeutic target. Therefore, the newest data related to TRPM3 have to be discussed and to be put in context as soon as possible to be up-to-date and to accelerate the translation from bench to bedside. The aim of this review is to highlight recent results and developments with particular focus on findings from studies involving ocular tissues and cells or peripheral neurons of rodents and humans." Read more at the source #DrGPCR #GPCR #IndustryNews

protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many Here, we determine that differential subcellular signaling contributes to the biased signaling generated Endosomal signaling is critical for biased activation of G proteins, β-arrestins, and extracellular-signal-regulated

Biased agonism is a phenomenon where different ligands acting on the same receptor trigger distinct signaling revealing that different ligands can stabilize distinct receptor conformations, leading to diverse signaling These differences in signaling profiles can have significant physiological implications. Christopoulos, Signalling bias in new drug discovery: detection, quantification and therapeutic impact AZIETAKU, J.T., Profiling Glucagon-Like Peptide -1 Receptor Transducer Coupling, Signalling and Biased

protein-coupled receptor kinase type 2 (GRK2) and β-arrestin2 are representative proteins that regulate the transduction and trafficking of G protein-coupled receptor (GPCR) signaling. The kinase GRK2 and the multifunctional scaffolding protein β-arrestin2 are key integrated signaling

of the largest and most vital families of cell surface receptors, playing a pivotal role in cellular signaling and chemokine signaling, extending to numerous other GPCR-regulated systems such as free fatty acid Allosteric agonists binding to intracellular sites can also promote G-protein signaling. Advances in understanding the structural and mechanistic aspects of biased GPCR signaling are crucial , such as β-arrestin and G-protein transducers, is important.

Depending on which ligand activates a receptor, it can engage different intracellular transducers. This 'biased signalling' paradigm requires that we now characterize physiological signalling not just Ligands eliciting biased signalling may constitute better drugs with higher efficacy and fewer adverse

The second messenger cyclic adenosine monophosphate (cAMP) is a key mediator in many GPCR signaling pathways In this regard, luminescence-based biosensors have revolutionized our ability to monitor GPCR signaling The GloSensor™ cAMP assay enables real-time monitoring of signaling downstream of many GPCRs. As well, the GloSensor-22F biosensor had a superior signal-to-background ratio and the effect of temperature Nevertheless, the GloSensor™ cAMP assay can be applied to analyze signaling by a wide range of GPCRs

effect through the activation of C5aR1, chemotactic receptor 1, and triggers the G protein-coupled signaling By comparing two C5aR receptors C5aR1 and C5aR2 we explained differences between their signaling pathways By means of molecular dynamics we explained why C5aR2 cannot transduce signal through the G protein pathway

GPCR Symposia Our upcoming symposium on March 15th is about GPCR activation and signaling. GPCR signaling bias: an emerging framework for opioid drug development Structural and functional insight pathway The non-nutritive sweetener sucralose increases β-arrestin signaling at the constitutively active orphan G protein-coupled receptor GPR52 Endosome positioning coordinates spatially selective GPCR signaling GRK5 promoted renal fibrosis via HDAC5/Smad3 signaling pathway Non-canonical G protein signaling GPCR

are present in a range of conformations, and the binding of a ligand, as well as interactions with signaling binding sites activated by peptides or proteins, and the disruption of natural spatial and temporal signaling therefore having the potential to maintain the temporal and spatial aspects of natural physiological signaling The significance of spatio-temporal attributes in signaling is demonstrated in processes like neurotransmission and chemokine signaling, extending to numerous other GPCR-regulated systems such as free fatty acid

Arora, J Silvio Gutkind, and Francesco Raimondi for their work on The landscape of cancer-rewired GPCR signaling gastrulation suggests roles in multiple morphogenetic events and regulation by AbdA GPCR Activation and Signaling biologics Lipid mediators in neutrophil biology: inflammation, resolution and beyond Exploring GPCR signaling cell lines to dissect complexity of GPCR signaling Structural and Molecular Insights into GPCR Function 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling

protein kinase B (AKT), nuclear factor kappa-B (NF-κB), extracellular regulated protein kinases (ERK1/2), signal transducer and activator of transcription 3 (STAT3), cyclic adenosine monophosphate (cAMP), Ras homolog protein activated by cAMP (Epac), and transient receptor potential ankyrin subtype 1 protein (TRPA1) signaling

August 2022 "G-protein-coupled receptors (GPCRs) receive signals from ligands with different efficacies , and transduce to heterotrimeric G-proteins to generate different degrees of physiological responses Cellular functional studies with mutations of β1-AR residues show effects on the cellular signaling from

contributor, for his article Class B1 GPCR Dimerization: Unveiling Its Role in Receptor Function and Signaling the Year at the Citeline Japan Awards 2024 GPCR therapies: Eight promising biotechs hacking the cell signaling /Structural Biologist Senior Scientist/Staff Scientist, Computational Chemistry GPCR Activation and Signaling receptors GPCRs in Neuroscience Astrocyte Gi-GPCR signaling corrects compulsive-like grooming and anxiety-related Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches Altered PLCβ/IP3/Ca2+ Signaling

Receptor "G protein-coupled receptors (GPCRs) constitute the largest class of membrane proteins that transduce signals across the plasma membrane and orchestrate a multitude of physiological processes within cells simulation approaches, that membrane cholesterol acts as a key regulator of organization, dynamics, signaling

Robert Lefkowitz for their work on GPCRs: from radioligand binding to cellular signaling Dr. Next week, on March 15th, we are hosting a symposium on GPCR activation and signaling. via single amino acid substitution G protein-coupled receptors: from radioligand binding to cellular signaling Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury GPCRs in pathway Blockade of vasoactive intestinal peptide receptor 2 (VIPR2) signaling suppresses cyclin D1-

., for their study on   Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected , location bias, signaling bias). Let’s dive into the   Classified GPCR News  from July 15th to 21st, 2024 GPCR Activation and Signaling Conformational dynamics underlying atypical chemokine receptor 3 activation RhoA-mediated G12-G13 signaling maintains muscle stem cell quiescence and prevents stem cell loss Activation of Polycystin-1 Signaling

., for their research on GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the in adhesion G protein-coupled receptors GPCR Activation and Signaling A-Kinase-Anchoring-Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade Allatotropin (AT) related peptides neuroprotective and neurogenic properties GPCRs in Oncology and Immunology Chemoattractant receptor signaling

Fine-tuning GPCR signaling: conformational dynamics and intracellular responses GPCR signaling is a complex Apart from G proteins, GPCRs engage other effectors for signaling modulation. as MAPK signaling (Song, X. et al. 2009, Coffa, S. et al. 2011). The diversity in GPCR signaling regulation suggests an individualized control mechanism. Despite multifocal signaling, recent studies indicate that signaling occurs within a 100 nm range from

β 2-Adrenergic Receptor Coordinates β -Arrestin Interaction G protein-coupled receptors (GPCRs) transduce a diverse variety of extracellular stimuli into intracellular signaling. Despite decades of research on the signaling consequences of molecule-receptor interactions, conformational 2AR) is a prototypical and extensively studied GPCR that can provide insight into this aspect of GPCR signaling pocket formed by transmembrane domains 2, 3, and 7 in GPCR regulation that may contribute to biased signaling