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Chemical communication controls a wide range of behaviors via conserved signaling networks. In this study, we investigated the role of chemical signaling in axon regeneration in Caenorhabditis Therefore, the ascaroside signaling system provides a unique example of a signaling molecule that regulates However, it remains unclear what signals activate the EGL-30 pathway in axon regeneration. Thus, ascaroside signaling promotes axon regeneration by activating the GPCR-Gqα pathway.

Career opportunities:  Discovery biology roles and training paths in GPCR signaling. Must-read publications:  Emerging targets, signaling dynamics, and acid-sensing receptors in disease. GPCR Podcast: Leadership, Impact, and GPCR Signaling with Dr. Michelle Halls dissects how spatial GPCR signaling shifts discovery—and how leadership, mentorship, and From cAMP to femtomolar ligands, she unpacks a career at the edge of precision signaling.

Fibroblasts from SSc patients exhibit a specific signalling and reactivate developmental pathways and Pharmacological interventions, although for other indications, are already in clinical use to address pathologic signalling

Deficiency of β-arrestin2 alleviates apoptosis through GRP78-ATF6-CHOP signaling pathway in primary Sjögren's First, excessive activation of β-arrestin2 and GRP78-ATF6-CHOP apoptosis signaling were detected in specimens In vivo, we found that inhibition of GRP78-ATF6-CHOP apoptosis signaling improved ESS symptoms, and the indices, and improved tissue integrity in the ESS model by downregulating GRP78-ATF6-CHOP apoptosis signaling In addition, β-arrestin2 depletion downregulated GRP78-ATF6-CHOP apoptosis signaling to alleviate cell

August 2022 "Emerging evidence suggests that G protein-coupled receptor (GPCR) kinases (GRKs) are associated with the pathophysiology of Alzheimer's disease (AD). However, GRKs have not been directly implicated in regulation of the amyloid-β (Aβ) pathogenic cascade in AD. Here, we determine that GRKs phosphorylate a non-canonical substrate, anterior pharynx-defective 1A (APH1A), an integral component of the γ-secretase complex. Significantly, we show that GRKs generate distinct phosphorylation barcodes in intracellular loop 2 (ICL2) and the C terminus of APH1A, which differentially regulate recruitment of the scaffolding protein β-arrestin 2 (βarr2) to APH1A and γ-secretase-mediated Aβ generation. Further molecular dynamics simulation studies reveal an interaction between the βarr2 finger loop domain and ICL2 and ICL3 of APH1A, similar to a GPCR-β-arrestin complex, which regulates γ-secretase activity. Collectively, these studies provide insight into the molecular and structural determinants of the APH1A-βarr2 interaction that critically regulate Aβ generation." Read more at the source #DrGPCR #GPCR #IndustryNews

GPCR Weekly News Free Edition—your clear, credible signal in a noisy field. You’ll learn how to: Solve the override vs. finesse dilemma:  When orthosterics hijack the signal vs Instead, the signal came clean, scalable, and unmistakably real. It wasn’t luck. Cleaner data:  higher signal-to-noise ratios sharpen CNS assays. Acting on the right signals today shapes tomorrow’s breakthroughs—and avoids slowdowns others won’t see

Watch Episode 174 Most scientists are taught to aim for precision and control. But what if that mindset blocks the very breakthroughs we seek? Dr. Eric Trinquet, a veteran innovator behind functional GPCR assays like HTRF and IP-One, believes rigid thinking is the enemy of discovery. In this podcast, he lays out the mindset that helped shape products used across biotech and academia—and why play, failure, and surprise are not risks to manage, but fuel to harness. If you’re building tools or careers in GPCR science, this is your playbook. The Innovation Trap: Why Most Scientists Think Too Narrowly Eric doesn’t mince words: many junior scientists don’t give themselves permission to explore. They think too narrowly, focus too early, and equate unexpected results with failure. This mindset, he argues, suffocates innovation. He knows the cost firsthand. “You can try, try, try—and fail, fail, fail,” Eric says. But those failures are where new paths emerge, often leading to transformative tools like the IP1 assay and Tag-lite. Instead of chasing linear progress, Eric encourages young scientists to stay playful longer—embracing both strategy and serendipity. A Quote That Stuck: “Be rigorous, but not too much. Frame your strategy, then let the serendipity occur.” — Dr. Eric Trinquet Built to Fail, Built to Win: Inside the IP1 Assay Origin Story The IP-One assay didn’t emerge from a master plan. It began with an unmet need: how to track Gq-coupled GPCR activity without the mess of calcium flux or radioactive columns. Eric and his team rejected the calcium route entirely. Instead, they focused on equilibrium-based assays and zeroed in on IP1 accumulation—pioneering a clean, high-throughput alternative. The real challenge? Convincing the field it worked. It took data, yes—but also a deep partnership with GPCR legend Terry Kenakin to bridge industry credibility with pharmacological rigor. Why This Matters: IP-One helped set a new gold standard for functional GPCR assays—shifting how compounds are evaluated for efficacy and bias. The pHSense Breakthrough: Two Dimensions of Discovery pHSense wasn’t built in a vacuum—it was born from decades of groundwork in rare earth chemistry and a “what if” mentality. Originally developed as ultra-bright lanthanide probes, the team realized they could tune these molecules to become exquisitely sensitive to pH changes. The innovation? Dual control: not just brightness but fluorescence lifetime, with drastic shifts as pH drops. That opened the door to something rare in functional pharmacology: plate-based GPCR internalization tracking that rivals (and sometimes beats) imaging or flow cytometry. Mini Timeline 🎯 Early 2000s: Trinquet leads IP1 & Tag-lite development 🧪 Mid-2010s: Rare-earth scaffold work begins 🔬 2023: pHSense probes optimized for dual pH response ✅ 2024: Endogenous GLP-1 internalization shown in beta cells 🚀 2025: Revvity launches pHSense A Day That Changed Everything: The Endogenous Receptor “Aha” Eric’s second “aha” moment with pHSense came the day his team showed internalization of endogenous GLP-1 receptors in rat beta cells—with no overexpression, no imaging, and no pharmacological interference. “We did a full dose-response and saw antagonism—all in one plate-based assay. That’s the day I knew we had something no one else had.” That result wasn’t just a technical win. It validated the broader goal: giving scientists tools to study receptors in their native, unmodified state—unlocking new questions about constitutive activity, agonist-induced internalization, and cellular dynamics. 🔄 What Changed After This Data: Trinquet pushed pHSense toward rapid commercialization—pivoting it from a research probe into a full product line. From Theory to Tool: How Great Products Get Built pHSense didn’t materialize overnight. It’s the product of layered collaborations—with Durham University chemist David Parker on the probe chemistry, and with Jean-Philippe Pin’s team in Montpellier to validate biological performance. Eric is clear: real innovation requires real partnerships. It also requires months—often years—of decisions, missteps, and refinements. From probe solubility to photophysics, from tag strategies to model systems, every variable was debated, tested, and validated. For Early-Career Scientists: Don’t confuse “final product” with overnight success. The catalog number is the last step in a years-long journey filled with messy iterations. Advice for the Next Generation: Don’t Over-Rationalize So what does Eric tell young scientists who want to build breakthrough products? “Don’t over-rationalize,” he says. At early stages, breadth matters more than precision. Cast a wide net. Follow anomalies. Build theories, but be ready to toss them. It’s a mindset shaped by decades in the lab—but it’s also a warning. Product development isn’t just about science. It’s about timing, teaming, testing, and failing smarter. 🚀 Why This Matters: Whether you’re launching a tool, starting a biotech, or running an academic lab—your mindset, not just your science, will determine what gets built. Want to hear Dr. Trinquet tell the story in his own words? 🎧 Listen to the full podcast episode here ⸻ More about Revvity pHSense Reagents GPCR Reagents Revvity on Dr. GPCR   Dr. GPCR X Revvity Collaboration ⸻ Want more like this? 👉 Join the Dr. GPCR Premium Ecosystem  for behind-the-scenes access to GPCR innovators, exclusive deep-dives, and practical tools to accelerate your research or career. 👥 Build connections. 🧪 Get insights. 🎧 Stay ahead.

Further investigation of the signaling pathways downstream of GPR183 is needed to support the development GPR183-induced mechano-allodynia was associated with significant activation of MAPKs (extracellular signal-regulated Our findings provide novel mechanistic insight into how GPR183 signaling in the spinal cord produces We found that 7α,25-OHC-induced allodynia is dependent on MAPK and NF-κB signaling pathways and results This study provides a first insight into how GPR183 signaling in the spinal cord is pronociceptive."

initially identified as a PAR2 antagonist, is a bona fide agonist of PAR2 that induces unique cellular signaling phosphorylation of MAPKs, but in a delayed and sustained manner compared to the rapid and transient signals results revealed that GB83 is a bona fide agonist of PAR2 that uniquely modulates PAR2-mediated cellular signaling

compounds with the highest affinities were demonstrated to be negative allosteric modulators of mGlu5 signaling

Join us for the first virtual cafe talk to hear about the amazing work that Dr. Brian Arey is doing. https://www.ecosystem.drgpcr.com/dr-gpcr-virtual-cafe/ #gpcr #drgpcr #virtualcafe

October 2022 Intermolecular Interactions in G Protein-Coupled Receptor Allosteric Sites at the Membrane Interface from Molecular Dynamics Simulations and Quantum Chemical Calculations "Allosteric modulators are called promising candidates in G protein-coupled receptor (GPCR) drug development by displaying subtype selectivity and more specific receptor modulation. Among the allosteric sites known to date, cavities at the receptor-lipid interface represent an uncharacteristic binding location that raises many questions about the ligand interactions and stability, the binding site structure, and how all of these are affected by lipid molecules. In this work, we analyze interactions in the allosteric sites of the PAR2, C5aR1, and GCGR receptors in three lipid compositions using molecular dynamics simulations. In addition, we performed quantum chemical calculations involving the symmetry-adapted perturbation theory (SAPT) and the natural population analysis to quantify the strength of intermolecular interactions. We show that besides classical hydrogen bonds, weak polar interactions such as O-HC, O-Br, and long-range electrostatics with the backbone amides contribute to the stability of allosteric modulators at the receptor-lipid interface. The allosteric cavities are detectable in various membrane compositions. The availability of polar atoms for interactions in such cavities can be assessed by water molecules from simulations. Although ligand-lipid interactions are weak, lipid tails play a role in ligand binding pose stability and the size of allosteric cavities. We discuss physicochemical aspects of ligand binding at the receptor-lipid interface and suggest a compound library enriched by weak donor groups for ligand search in such sites." Read more at the source #DrGPCR #GPCR #IndustryNews

Must-read publications:  Stay updated on cutting-edge research, including the potentiation of GPCR signaling Catherine’s research, blending GPCR signaling studies with public health data, offers critical insights intersect—and why pharmacologists are critical in addressing this crisis ➤ Call for Papers – GPCRs: Signal Transduction Volume II With over 21,000 views  and 7,785 downloads  from Volume I, the Signal Transduction Those who act on the right signals today will lead tomorrow’s breakthroughs—and avoid delays others won

. ✅ Insight into Consequences:  How binding sites determine receptor state shifts, signaling outcomes Orthosteric ligands preempt  natural signaling; they “take over” receptor behavior, forcing physiology , act more like tuning knobs—modulating receptor ensembles in partnership with the system’s ongoing signaling For drug discovery teams navigating safety margins, biased signaling, and combination therapy design, This means you can design molecules that potentiate beneficial pathways without shutting down basal signaling

relationship between the conformational change of the receptor because of the mutation and related downstream signaling understanding of the relationship between the changed conformation of the receptor and consequently activated signaling

We have previously reported that the MC4R forms homodimers, affecting receptor Gs signaling properties In this study, we analyzed effects of inhibiting homodimerization on Gq/11 signaling using previously Gq/11 signaling of chimeric receptors was analyzed using luciferase-based reporter gene (NFAT) assays Results demonstrate an improvement of alpha-MSH-induced NFAT signaling of chimeras, reaching the level of setmelanotide signaling at wild-type MC4R (MC4R-WT).

activity by anosmin 1, since this protein is able to enhance the activation of the ERK1/2 (extracellular signal-regulated

We discuss ligand binding, signaling, and structures of the vGPCRs in light of robust differences from

focus on the relatively less well-studied effects of GPCRs in cardiac fibroblasts, focusing on key signaling We also review the hierarchy of signaling events driving the fibrotic response and the communications We discuss how such events may be distinct depending on where the GPCRs and their associated signaling Finally, we explore what such connections between the cell surface and nuclear GPCR signaling might mean

While others pivoted, Sokhom went deeper: refining assays, exploring signaling bias, and building a robust Advances in biased signaling, allosterism, and endosomal signaling have opened new therapeutic frontiers A Career Built on Consistency From CGRP receptor antagonists at BMS to opioid receptor research at Alkermes

Denied stronger medication in the midst of the opioid crisis, he turned to the one place that still offered But everything changed when his recurring pain — and the rigid protocols around opioid prescription — There, he learned how to frame pain not just as a symptom, but as a signal — and a scientific challenge

The S339fs5 and R334X mutants exhibited significantly increased signaling compared to wild type CXCR4 including agonist-promoted calcium flux and extracellular signal-regulated kinase activation. together, these studies identify a new WHIM syndrome mutant, CXCR4-S339fs5, that promotes enhanced signaling

bias "Within the intestine, the human G protein-coupled receptor (GPCR) GPR35 is involved in oncogenic signaling cells to thoroughly profile both GPR35 isoforms for constitutive and ligand-induced activation and signaling

September 2022 "GPCR signaling and function depend on their associated proteins and subcellular locations they connect a large number of diverse proteins to form signaling networks. We found that some agonist-induced GPCR/14-3-3 signal intensities can rapidly decrease. could also be paralleled with GPCR/β-arrestin-2 signals, indicating diminished levels of GPCR/signal a new approach for GPCR drug development by modulating GPCR/14-3-3 signals temporally."

in the role of GPCRs in lifespan are those that mimic dietary restriction, those related to insulin signaling

receptors (GPCRs) about a novel biosensor shed light on the endosomal proteome associated with the δ-opioid DNAJC13 is crucial to the trafficking of DOR, facilitating its downregulation and influencing cellular signaling real-time opens new avenues for understanding drug tolerance and resistance, particularly in the context of opioid As the opioid crisis continues to challenge public health, insights gained from this research could inform

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

2022 "Heterotrimeric G proteins couple activated G protein-coupled receptors (GPCR) to intracellular signaling of GPCR activation upon acquiring mutations that prevent GTPase activity and result in constitutive signaling YM-254890 (YM) can inhibit signaling by both GPCR-activated wild type αq and GPCR-independent αqQ209L Treatment of cells with YM failed to inhibit signaling by these PM-restricted αqQ209L. GPCR-dependent signaling by PM-restricted wild type αq is strongly inhibited by YM, demonstrating that

papers—it demands access to the right frameworks and expert insights that separate the noise from the signal Breakthroughs this week: Glucagon-like Peptide-1 Receptor (GLP-1R) Signaling; Proximity-Dependent Proteomics Upcoming events:  Get details on the "neuroGPCR" symposium focusing on receptor signaling and a platform Expand your computational toolkit ➤ Call for Papers: GPCRs: Signal Transduction, Volume II Building on the success of its first volume, the research topic "GPCRs: Signal Transduction: Volume II" is now open

activity results in the generation of diacylglycerol and inositol trisphosphate, which are downstream signal In this article, we describe the signal transduction elements that regulate PLC gene expression. The discussion is focused on the norepinephrine- α1-adrenoceptor signaling pathway and downstream signaling the expression of PLC isozymes with the suggestion that PLC activities may be part of a coordinated signaling