September 2022 "The activation of phospholipase C (PLC) is thought to have a key role in the cardiomyocyte

Here, we provide evidence that distal carboxyl-terminal tail (C-tail), but not proximal, phosphorylation site-directed mutagenesis and bioluminescence resonance energy transfer approaches that distal, not proximal, C-tail In addition, we show that GPCRs that have similarly positioned C-tail phosphoresidues are also able to However, although necessary for some GPCRs, we found that distal C-tail sites might not be sufficient In conclusion, this study provides evidence that distal C-tail phosphorylation sites specify GRK-βarrestin-mediated

October 2022 Coincident Regulation of PLCβ Signaling by Gq-Coupled and μOpioid Receptors Opposes Opioid- Mediated Antinociception "Pain management is a significant problem worldwide. The current frontline approach for pain-management is the use of opioid analgesics. The primary analgesic target of opioids is the μ-opioid receptor (MOR). Deletion of phospholipase Cβ3 (PLCβ3), or selective inhibition of Gβγ regulation of PLCβ3, enhances the potency of the antinociceptive effects of morphine suggesting a novel strategy for achieving opioid sparing effects. Here we investigated a potential mechanism for regulation of PLC signaling downstream of MOR in HEK293 cells and found that MOR alone could not stimulate PLC, but rather required a coincident signal from a Gq coupled receptor. Knockout of PLCβ3, or pharmacological inhibition of its upstream regulators, Gβγ or Gq, ex vivo in periaqueductal gray (PAG) slices increased the potency of the selective MOR agonist DAMGO in inhibiting presynaptic GABA release. Finally, inhibition of Gq-GPCR coupling in mice enhanced the antinociceptive effects of morphine. These data support a model where Gq and Gβγ-dependent signaling cooperatively regulate PLC activation to decrease MOR-dependent antinociceptive potency. Ultimately this could lead to identification of new non-MOR targets that would allow for lower dose utilization of opioid analgesics. " Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE

Authors Charles H Williams , Leif R Neitzel , Jessica Cornell , Samantha Rea , Ian Mills , Maya S Silver , Jovanni D Ahmad , Konstantin G Birukov , Anna Birukova , Henry Brem , Betty Tyler , Eli E Bar , Charles C Hong Source Contribute to the GPCR News Coming soon Become a Contributor Classified GPCR News Call

Principles of Pharmacology in Drug Discovery II Advanced Methods for the Optimization of Candidate Selection Dr. Terry Kenakin Advanced Methods for the Optimization of Candidate Selection This course continues with the basics learned in Course 1 and extends the ideas to apply GPCR utilization in drug therapy . Specifically, the ideas discussed cover the complex pleiotropic behaviors of GPCRs and how these may be exploited for new drug discovery. Receptor data shows how GPCR control of cellular function goes far beyond simple second messenger production (i.e., calcium, cAMP), and these new behaviors are being used to create novel GPCR therapies. The five-lecture series describes essential additional elements to GPCR discovery programs that extend the discovery process and increase therapeutic opportunity. Registrants will learn: The powerful applications of new cellular assays to determine GPCR ligand behavior in different functional systems. Understanding real-time kinetics to predict activity and in vivo target coverage. New ligands and new GPCR behaviors that produce unique drug profiles (i.e. intracellular ligands and signaling, location bias, signaling bias). Modules October 31st: The Eyes to See- The Importance of Pharmacologic Assays. November 7th: Drug Disposition in Physiological Tissues as a Therapeutic Variable. November 14th: The Application of GPCR Ligand Kinetics to Candidate Design. November 21st: Unconventional GPCR Ligands as Drugs. December 5th: Unique Exploitable GPCR-Ligand Behaviors for Therapeutic Benefit. Registrations start on Monday, July 15th, 2024 Classes will be live from Zoom on Thursdays from 10 am to 11:30 am EST. Sessions will include a 1-hour live lecture plus 30 minutes of Q&A. Participants who complete the course will get an online certification signed by the professor and the Dr.GPCR Team. A splendid time is guaranteed for all. What are the main objectives of the course? Allow registrants to appreciate the great versatility of GPCRs and how small molecules can affect their behavior for therapeutic benefit. What will students gain from taking this course? Learn how to therapeutically exploit GPCRs (Physiology’s ‘Swiss Army Knife’) wide repertoire of ways to control cell function. Apply unique pharmacologic assays and unconventional ligands to unveil GPCR activities. Adjust ligand kinetics and tissue disposition for optimal therapeutic activity. Are there any specific textbooks or readings students should be aware of? Pharmacology in Drug Discovery and Development (3rd ed.) T>P> Kenakin, Elsevier or ''A Pharmacology Primer' (6th ed.) T.P. Kenakin, Elsevier. Register today! Early-bird registration is over. Principles of Pharmacology II $ 675 675$ +$20.25 Transaction fee Advanced Methods for the Optimization of Candidate Selection Valid for 6 months Select Subscribe to Dr. GPCR's Newsletter to be the first to know about the next courses! What would you like to learn today?

Principles of Pharmacology in Drug Discovery I Techniques for Effective Lead Optimization of Candidate Molecules Dr. Terry Kenakin Techniques for Effective Lead Optimization of Candidate Molecules GPCRs have been and arguably still are the most prolific and fertile therapeutic drug targets; this course describes the essential pharmacologic techniques and knowledge required to create a GPCR Target Program aimed at the discovery of new Drugs. The course will focus on the methods used to quantify GPCR ligand activity (agonists, antagonists, modulators) and the process of characterizing the mechanism of action of ligands to enable the prediction of activity in vivo systems. In general, registrants will receive a comprehensive understanding of the unique science of pharmacology and how it can describe drug action in system-independent ways. Registrants will learn: Essentials of measuring pharmacologic activity of ligands (affinity, efficacy, co-operativity). Application of this knowledge to determine the mechanism of action of new GPCR ligands. The required elements of a comprehensive and effective GPCR Discovery. Modules: October 3rd: GPCR Project Initiation and Design for Discovery of New Molecules. October 10th: Drug Affinity: Measurement of Antagonism (Binding and Function) / Classifying Antagonists. October 17th: Agonists and Efficacy: A New World of GPCR Efficacies / Biased Signaling. October 24th: Allosteric Modulators: NAMs, PAMs, Special Properties, Methods to quantify the allosteric effect. Registrations start on Monday, July 15th, 2024. Classes will be live from Zoom on Thursdays from 10 am to 11:30 am EST. Sessions will include a 1-hour live lecture plus 30 minutes of Q&A. Participants who complete the course will get an online certification signed by the professor and the Dr.GPCR Team. A splendid time is guaranteed for all. Registration over Subscribe to Dr. GPCR's Newsletter to be the first to learn about the next courses! What would you like to learn today?