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December 2021 "Meet Peter McNamara, Ph.D., Tectonic’s SVP, Head of Research. Peter joined Tectonic to help chart new territory in GPCR science. We’re glad to have Peter's dedication, experience, and passion in building innovative therapeutics."

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

Peter Banks, Scientific Director at BioTek Instruments! Learn about his career today!

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

2022 Use of CRISPR/Cas9-edited HEK293 cells reveals that both conventional and novel protein kinase C activation of PKC and mutation of rat mGlu5a Ser901, a PKC-dependent phosphorylation site in the receptor C-tail

G protein-coupled receptors (GPCRs) are among the most promising drug targets. They often form homo- and heterodimers with allosteric cross-talk between receptor entities, which contributes to fine-tuning of transmembrane signaling. Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their physiological roles and validate them as drug targets. Here, we examined the mode of action of positive allosteric modulators (PAMs) that bind at the interface of the transmembrane domains of the heterodimeric GABAB receptor. Our site-directed mutagenesis results show that mutations of this interface impact the function of the three PAMs tested. The data support the inference that they act at the active interface between both transmembrane domains, the binding site involving residues of the TM6s of the GABAB1 and the GABAB2 subunit. Importantly, the agonist activity of these PAMs involves a key region in the central core of the GABAB2 transmembrane domain, which also controls the constitutive activity of the GABAB receptor. This region corresponds to the sodium ion binding site in class A GPCRs that controls the basal state of the receptors. Overall, these data reveal the possibility of developing allosteric compounds able to specifically modulate the activity of GPCR homo- and heterodimers by acting at their transmembrane interface. Read full article

The TAS1R2 and TAS1R3 subunits are members of a small family of class C GPCRs whose members share the

September 2022 "In the Wnt-β-catenin pathway, Wnt binding to Frizzled (Fzd) and LRP5 or LRP6 (LRP5/6) co-receptors inhibits the degradation of the transcriptional coactivator β-catenin by recruiting the cytosolic effector Dishevelled (Dvl). Polymerization of Dvl at the plasma membrane recruits the β-catenin destruction complex, enabling the phosphorylation of LRP5/6, a key step in inhibiting β-catenin degradation. Using purified Fzd proteins reconstituted in lipid nanodiscs, we investigated the factors that promote the recruitment of Dvl to the plasma membrane. We found that the affinity of Fzd for Dvl was not affected by Wnt ligands, in contrast to other members of the GPCR superfamily for which the binding of extracellular ligands affects the affinity for downstream transducers. Instead, Fzd-Dvl binding was enhanced by increased concentration of the lipid PI(4,5)P2, which is generated by Dvl-associated lipid kinases in response to Wnt and which is required for LRP5/6 phosphorylation. Moreover, binding to Fzd did not promote Dvl DEP domain dimerization, which has been proposed to be required for signaling downstream of Fzd. Our findings suggest a positive feedback loop in which Wnt-stimulated local PI(4,5)P2 production enhances Dvl recruitment and further PI(4,5)P2 production to support Dvl polymerization, LRP5/6 phosphorylation, and β-catenin stabilization." Read more at the source #DrGPCR #GPCR #IndustryNews

Latrophilin-1 drives neuron morphogenesis and shapes chemo- and mechanosensation-dependent behavior in C. nematode Caenorhabditis elegans can also function independently of their seven-transmembrane domain and C Here, we show that Latrophilin-1 acts in trans to mediate morphogenesis of sensory structures in the C.

Affects Ca 2+ Sensing but Not G Protein Interaction "The calcium-sensing receptor is a homodimeric class C

K., Gellman, S. H., Pautsch, A., Steyaert, J., Weis, W. I., & Kobilka, B. K. (2011). C., Ring, A. ., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C., Sexton, P. ., Felder, C. C., Gmeiner, P., Steyaert, J., Weis, W. I., Garcia, K. C., Wess, J., & Kobilka, B. L., & Garcia, K. C. (2015). Structural biology.

reveal recognition motifs for the MRGPRD GPCR Chunyu Wang ,  Yongfeng Liu ,  Marion Lanier ,   Brian K adenocarcinoma, β-blockers and antihistamines: A clinical trial is needed Jillian G Baker ,  Erica K Sloan ,   Kevin Pfleger ,  Peter J McCormick , Cristina Salmerón ,   Paul A Insel PGxDB: an interactive at two distinct sites of a human bitter taste GPCR Lior Peri ,  Donna Matzov ,  Dominic R Huxley ,   Peter Gmeiner ,  Peter J McCormick ,  Dorothee Weikert ,  Masha Y Niv ,  Moran Shalev-Benami , et al.

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Although this study has limitations, such as the absence of the flexible distal C-tail of βArr2 in the M., Medel-Lacruz, B., Baidya, M., Makarova, M., Mistry, R., Goulding, J., Drube, J., Hoffmann, C., Owen K., Selent, J., Hill, S. J., & Calebiro, D. (2023). M., Kawakami, K., Masureel, M., Maeda, S., Garcia, K. C., von Zastrow, M., Inoue, A., & Kobilka, B. K. (2022). Membrane phosphoinositides regulate GPCR-β-arrestin complex assembly and dynamics.

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K., Bouvier, M., & Babu, M. M. (2023). K., Hoppe, N., Huang, X. P., Macdonald, C. B., Mehrota, E., Grimes, P.

Reference Araya, C. L., & Fowler, D. M. (2011). K., Hoppe, N., Huang, X.-P., Macdonald, C. B., Mehrotra, E., Patrick Rockefeller Grimes, Zahm, A. G., & Eckert, C. A. (2020). Predicting Drug Resistance Using Deep Mutational Scanning.

consequences of spatial, temporal and ligand bias of G protein-coupled receptors Antonios Drakopoulos, Peter consequences of spatial, temporal and ligand bias of G protein-coupled receptors Inverse Regulation of C-C

activated, ERKs translocate to the nucleus, phosphorylating various transcription factors, including ETS, c-Jun Lu, N., & Malemud, C. J. (2019). K., Karnik, S. S., Hunyady, L., Luttrell, L. M., & Lefkowitz, R. J. (2003).

Cell death signaling in Anopheles gambiae initiated by Bacillus thuringiensis Cry4B toxin involves Na+/K+ Transforming Growth Factor β-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts GPCRs in Neuroscience System-wide mapping of peptide-GPCR interactions in C. elegans GPCR

This week's highlight includes congrats to: Makaía M Papasergi-Scott, Peter Gmeiner, Brian K Kobilka,

GPCR Activation and Signaling G protein activation via chemokine (C-X-C motif) receptor 4 and α1b -adrenoceptor Immunology Minireview: functional roles of tissue kallikrein, kinins, and kallikrein-related peptidases in lung

In silico analyses done in this study with the NetOGlyc 4.0 prediction algorithm (Steentoft C et al. a single sialic acid, although, in rare cases glycans can carry polysialylation (PolySia) (Mindler K phosphosulfate (PAPS) donor to the hydroxyl group of a tyrosine residue of the protein chain (Seibert C glycosaminoglycans which have an established role in chemokine gradients and oligomerization (Deshauer C

., & Tate, C. G. 2021). hydrogen-deuterium exchange (HDX) mass spectrometry for time-dependent conformational insights (Komolov, K. proteins, presenting an array of effectors that could be recruited to GPCR–β-arrestin complexes (Xiao, K M. et al. 1999), while dual knockout is lethal (Schmid, C. L., & Bohn, L. M. 2009).

G-Protein Coupled Receptors), today announced the promotion of Senior Vice President, Head of Research, Peter

Don’t be surprised if you find yourself singing Daddy Yankee’s “Gasolina” from the top of your lungs PMID: 38758649 Member Simone Prömel’s lab shows that the nematode (C. elegans) homolog of CELSR, FMI- Bandekar with help from Nathan Zaidman and Abhishek K. Singh