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We obsess over target validation, signaling pathways, expression patterns, and disease relevance. of new chemical sources beyond natural agonist analogs Awareness of how GPCR allostery and biased signaling chemists learned early that modifying endogenous molecules — hormones, neurotransmitters, and metabolic signals Allostery and Biased Signaling Change the Game The most profound change in GPCR drug discovery is our (NAMs) — attenuate signaling Biased agonists  — favor one intracellular pathway over another These are

September 2022 Roles of Focal Adhesion Kinase PTK2 and Integrin αIIbβ3 Signaling in Collagen- and GPVI-Dependent Thrombus Formation under Shear "Glycoprotein (GP)VI and integrin αIIbβ3 are key signaling receptors The multiple downstream signaling pathways are still poorly understood. Peptides did not influence GPVI-induced aggregation and Ca2+ signaling in the absence of shear. This work thereby supports the role of PTK2 in integrin αIIbβ3 activation and signaling."

September 2022 GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome

protein-coupled receptor (GPCR) kinases (GRKs) and arrestins mediate GPCR desensitization, internalization, and signaling not proximal, phosphorylation of the chemokine receptor CXCR4 specifies βarrestin1 (βarr1)-dependent signaling not proximal, C-tail phosphorylation sites are required for recruitment of the adaptor protein STAM1 (signal-transducing adaptor molecule) to βarr1 and focal adhesion kinase phosphorylation but not extracellular signal-regulated this study provides evidence that distal C-tail phosphorylation sites specify GRK-βarrestin-mediated signaling

Are you ready to truly understand how pharmacologists predict whole-body drug response from a single experiment?   Terry Kenakin’s newest foundational lesson in Terry's Corner  cuts straight to it:   Why models are vital for translating lab data into clinical forecasts The 4 types of pharmacologic models (and when to use each) The truth about linear models: useful or misleading? How the Mass Action Law underpins nearly every model Future of Receptor Theory: Linkage vs. Probability Models   This is practical drug development expertise from Terry’s 40+ years of experience.   Beyond the lessons, Terry's Corner  is your exclusive gateway. Ecosystem Premium Members: Look for significant savings on this and other resources in your weekly Dr. GPCR News.   Elevate your pharmacology expertise. Unlock "Pharmacologic Models" now

Although numerous signals are known to regulate synapses, it remains unclear which signaling mechanisms referred to as "SynTAMs" for synaptic targeting molecules, that enable localized perturbations of cAMP signaling In vivo, suppression of postsynaptic cAMP signaling in CA1 neurons prevented formation of both Schaffer-collateral Retrograde trans-synaptic rabies virus tracing revealed that postsynaptic cAMP signaling is required adhesion-GPCRs drive synapse formation and produce cAMP, we suggest that spatially restricted postsynaptic cAMP signals

G protein-coupled receptor interactions and modification of signalling involving the ghrelin receptor In all cases, the receptor interaction changes downstream signalling and the responses to receptor agonists This review discusses the signalling mechanisms of GHSR1a alone and in combination with other GPCRs,

October 2022 Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of Gi/o signaling "Aims: Cardiac contractility, essential to maintaining proper cardiac output and circulation, is regulated by G protein-coupled receptor (GPCR) signaling. Previously, the absence of regulator of G protein signaling (RGS) 2 and 5, separately, was shown to cause Whether RGS2 and 5 redundantly control G protein signaling to maintain cardiovascular homeostasis is

Arrestins regulate a wide range of signaling events, most notably when bound to active G protein-coupled modulates Fgr activity with a hallmark bell-shaped concentration-dependence, consistent with a role as a signaling

correlate with three cholesterol molecules that play essential roles in conformation stabilization and signaling Thus, our data deepen the understanding of cholesterol modulation in GPCR (G protein-coupled receptor) signaling

potency — it hinges on where receptors actually are, how they internalize, and how tissues interpret signals Visualization tools redefine our understanding of signaling in intact metabolic tissues. Listen to the episode ➤ Quick Links Assess GPCR Biased Signaling of Agonist How GPCR Collaboration Built an Innovation Engine From Pipettes to Platforms: The Evolution of GPCR Research How GPCR Spatial Signaling Acting on the right signals today shapes tomorrow’s breakthroughs — and prevents delays others won’t

Lysophosphatidic Acid and Several Neurotransmitters Converge on Rho-Kinase 2 Signaling to Manage Motoneuron IME by TASK1 inhibition, stimulated ROCK2, and depressed background resting currents via Gαq/ROCK2 signaling

GPCRs share a common mechanism of action via the β-arrestin scaffolding signaling complexes, which not only serve to desensitize GPCRs by internalization, but also mediate multiple downstream signaling events As signaling via the GPCRs, β2-adrenergic receptor (β2AR), and metabotropic glutamate receptor 2 (mGluR2

August 2022 Dopamine D 1 receptor-mediated β-arrestin signaling: Insight from pharmacology, biology, behavior, and neurophysiology "The awareness of the potential importance of functional selectivity/biased signaling been to identify GPCR-selective ligands that have bias in G protein-dependent vs. β-arrestin related signaling important pharmacological, molecular, and cellular studies relevant to D1-mediated β-arrestin-related signaling translatability of cell and animal models to have more precise functional targeting to harness the value of this signaling

achieved for 6 by treatment with 1 µM CAN1404 for 24 h, and a corresponding increase in FSH-induced signaling

October 2022 "Psychedelics, also known as classical hallucinogens, affect processes related to perception, cognition and sensory processing mostly via the serotonin 5-HT2A receptor (5-HT2AR). This class of psychoactive substances, which includes lysergic acid diethylamide (LSD), psilocybin, mescaline and the substituted amphetamine 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), is receiving renewed attention for their potential therapeutic properties as it relates to psychiatric conditions such as depression and substance use disorders. Current studies focused on the potentially clinical effects of psychedelics on human subjects tend to exclude sex as a biological variable. Much of the understanding of psychedelic pharmacology is derived from rodent models, but most of this preclinical research has only focused on male mice. Here we tested the effects of DOI on head-twitch behavior (HTR) - a mouse behavioral proxy of human psychedelic potential - in male and female mice. DOI elicited more HTR in female as compared to male C57BL/6J mice, a sex-specific exacerbated behavior that was not observed in 129S6/SvEv animals. Volinanserin (or M100907) - a 5-HT2AR antagonist - fully prevented DOI-induced HTR in male and female C57BL/6J mice. Accumulation of inositol monophosphate (IP1) in the frontal cortex upon DOI administration showed no sex-related effect in C57BL/6J mice. However, the pharmacokinetic properties of DOI differed among sexes - brain and plasma concentrations of DOI were lower 30 and 60 min after drug administration in female as compared to male C57BL/6J mice. Together, these results suggest strain-dependent and sex-related differences in the behavioral and pharmacokinetic profiles of the 5-HT2AR agonist DOI in C57BL/6J mice, and support the importance of studying sex as a biological variable in preclinical psychedelic research." Read more at the source #DrGPCR #GPCR #IndustryNews

Intracellular calcium ([Ca2+]i) signaling is a critical regulator of chondrogenesis, chondrocyte differentiation Calcium (Ca2+) signaling is known to direct processes that govern chondrocyte gene expression, protein Control of chondrocyte/chondroprogenitor Ca2+ signaling has been attempted through mechanical and/or Synthetic signaling platforms permitting precise and selective Ca2+ signal transduction can improve dissection of the roles that [Ca2+]i signaling plays in chondrocyte behavior.

β-arrestin recruiting GPR84 agonists "In order to avoid a prolonged pro-inflammatory neutrophil response, signaling Among the family of GPCR kinases (GRKs) that regulate receptor phosphorylation and signaling termination

August 2022 "Background: Activation of signaling effectors by G-protein coupled receptors (GPCRs) depends Although studies have focused on the G-protein signaling state, the mechanism for β-arrestin signaling

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.

Objective: The goal of this study was to determine the glucometabolic effects of acute activation of Gs signaling Results: Acute stimulation of GsD signaling in SKM impaired glucose tolerance in lean and obese mice The acute metabolic effects of UCN2 were not mediated by SKM Gs signaling. Conclusions: Selective activation of Gs signaling in SKM causes an acute increase in blood glucose levels

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.

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

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

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

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