scholarly journals Activating autoantibodies against G protein-coupled receptors in narcolepsy type 1

2021 ◽  
Vol 77 ◽  
pp. 82-87
Author(s):  
Maija Orjatsalo ◽  
Eemil Partinen ◽  
Gerd Wallukat ◽  
Anniina Alakuijala ◽  
Markku Partinen
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Activating Autoantibodies ◽  
G Protein Coupled

Adrenomedullin: receptor and signal transduction

2002 ◽  
Vol 30 (4) ◽  
pp. 432-437 ◽  
Author(s):  
D. M. Smith ◽  
H. A. Coppock ◽  
D. J. Withers ◽  
A. A. Owji ◽  
D. L. Hay ◽  
...  
Keyword(s):  
G Protein ◽  
Vascular Tissue ◽  
G Protein Coupled Receptors ◽  
Type Ii ◽  
Calcitonin Gene ◽  
Adrenomedullin Receptor ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled ◽  
Chemical Cross Linking

Adrenomedullin is a vascular tissue peptide and a member of the calcitonin family of peptides, which includes calcitonin, calcitonin-gene-related peptide (CGRP) and amylin. Its many biological actions are mediated via CGRP type 1 (CGRP1) receptors and by specific adrenomedullin receptors. Although the pharmacology of these receptors is distinct, they are both represented in molecular terms by the type II family G-protein-coupled receptor, calcitonin-receptor-like receptor (CRLR). The specificity here is defined by co-expression of receptor-activity-modifying proteins (RAMPs). CGRP1 receptors are represented by CRLR and RAMP1, and specific adrenomedullin receptors by CRLR and RAMP2 or 3. Here we discuss how CRLR/RAMP2 relates to adrenomedullin binding, pharmacology and pathophysiology, and how chemical cross-linking of receptor-ligand complexes in tissue relates to that in CRLR/RAMP2-expressing cells. CRLR, like other type II family G-protein-coupled receptors, signals via Gs and adenylate cyclase activation. We demonstrated that adrenomedullin signalling in cell lines expressing specific adrenomedullin receptors followed this expected pattern.

Role of helix 8 in G protein-coupled receptors based on structure–function studies on the type 1 angiotensin receptor

2009 ◽  
Vol 302 (2) ◽  
pp. 118-127 ◽  
Author(s):  
John Huynh ◽  
Walter Glen Thomas ◽  
Marie-Isabel Aguilar ◽  
Leonard Keith Pattenden
Keyword(s):  
Structure Function ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Angiotensin Receptor ◽  
G Protein Coupled

scholarly journals Contribution of AT1R mechanoactivation to the arterial myogenic response and its regulation by RGS5 protein in skeletal muscle arterioles

2015 ◽  
Author(s):  
◽  
Kwangseok Hong
Keyword(s):  
G Protein ◽  
Mechanical Stimulus ◽  
G Protein Coupled Receptors ◽  
G Protein Signaling ◽  
Myogenic Response ◽  
Protein Signaling ◽  
Regulatory Molecule ◽  
Cytoskeleton Reorganization ◽  
G Protein Coupled

Although intracellular mechanisms underlying the arteriolar myogenic response have been well-defined, the mechanotransduction events transducing the mechanical stimulus remain unclear. Recently, ligand-independent activation of G protein-coupled receptors (in particular, the angiotensin II type 1 receptor; AT1R) has been suggested to play a major role in vascular smooth muscle mechanotransduction, thereby contributing to myogenic constriction. However, the downstream pathways following ligand-independent activation of the AT1R have not been clearly elucidated. Our studies provide pharmacological evidence that the mechanically activated AT1R generates diacylglycerol which in turn activates PKC that subsequently induces actin cytoskeleton reorganization for myogenic constriction. In terms of physiological roles, the arterial myogenic response acts to generate vascular tone, prevent capillaries from being damaged, and reduce edema due to high capillary hydrostatic pressure. Thus, an exaggerated AT1R-mediated myogenic constriction could conceivably contribute to vascular disorders. As a result, small arteries likely exhibit negative feedback regulatory mechanisms to prevent such an exaggerated myogenic response. In regard to this, we discovered that ligand-dependent or-independent activation of the AT1R causes trafficking of an important regulatory molecule, RGS5 (Regulators of G protein Signaling) protein, which may modulate Ang II or myogenic-mediated constriction by terminating Gq/11 protein-dependent signaling.

scholarly journals Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jenna Giubilaro ◽  
Doris A. Schuetz ◽  
Tomasz M. Stepniewski ◽  
Yoon Namkung ◽  
Etienne Khoury ◽  
...  
Keyword(s):  
G Protein ◽  
Cellular Responses ◽  
Receptor Trafficking ◽  
G Protein Coupled Receptors ◽  
Cancer Cell Proliferation ◽  
Small G Protein ◽  
In Silico Modeling ◽  
G Protein Coupled

AbstractInternalization and intracellular trafficking of G protein-coupled receptors (GPCRs) play pivotal roles in cell responsiveness. Dysregulation in receptor trafficking can lead to aberrant signaling and cell behavior. Here, using an endosomal BRET-based assay in a high-throughput screen with the prototypical GPCR angiotensin II type 1 receptor (AT1R), we sought to identify receptor trafficking inhibitors from a library of ~115,000 small molecules. We identified a novel dual Ras and ARF6 inhibitor, which we named Rasarfin, that blocks agonist-mediated internalization of AT1R and other GPCRs. Rasarfin also potently inhibits agonist-induced ERK1/2 signaling by GPCRs, and MAPK and Akt signaling by EGFR, as well as prevents cancer cell proliferation. In silico modeling and in vitro studies reveal a unique binding modality of Rasarfin within the SOS-binding domain of Ras. Our findings unveil a class of dual small G protein inhibitors for receptor trafficking and signaling, useful for the inhibition of oncogenic cellular responses.

scholarly journals Distinctive T Cell-suppressive Signals from Nuclearized Type 1 Sphingosine 1-Phosphate G Protein-coupled Receptors

2006 ◽  
Vol 282 (3) ◽  
pp. 1964-1972 ◽  
Author(s):  
Jia-Jun Liao ◽  
Mei-Chuan Huang ◽  
Markus Graler ◽  
Yong Huang ◽  
Hong Qiu ◽  
...  
Keyword(s):  
T Cell ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Compromised E-cadherin adhesion and epithelial barrier function with activation of G protein-coupled receptors is rescued by Y-to-F mutations in β-catenin

2008 ◽  
Vol 294 (3) ◽  
pp. L442-L448 ◽  
Author(s):  
Michael C. Winter ◽  
Sandra Shasby ◽  
D. Michael Shasby
Keyword(s):  
G Protein ◽  
Mdck Cells ◽  
Tyrosine Phosphatase ◽  
G Protein Coupled Receptors ◽  
Epithelial Barrier Function ◽  
L Cells ◽  
G Protein Coupled ◽  
Cad Cells ◽  
E Cadherin

Activation of the type 1 histamine (H1) or the type 2 protease-activated (PAR-2) G protein-coupled receptors interrupts E-cadherin adhesion and decreases the transepithelial resistance (TER) of epithelium. Several reports suggest that cadherin adhesive function depends on the association of cadherin with β-catenin and that this association is regulated by phosphorylation of tyrosines in β-catenin. We tested the hypothesis that loss of cadherin adhesion and compromise of TER on activation of the H1 or PAR-2 receptor is due to phosphorylation of tyrosines in β-catenin. L cells were stably transfected to express E-cadherin (L-E-cad cells) and H1 (L-H1-E-cad cells). L cells and Madin-Darby canine kidney (MDCK) cells constitutively express PAR-2. Stably transfected L-E-cad, L-H1-E-cad, and MDCK cells were also stably transfected with FLAG-tagged wild-type (WT) or mutant β-catenin, converting tyrosine 142, 489, or 654 to the nonphosphorylatable mimetic, phenylalanine (WT, Y142F, Y489F, or Y654F). Activation of H1 or PAR-2 interrupted adhesion to an immobilized E-cadherin-Fc fusion protein of L-H1-E-cad, L-E-cad, and MDCK cells expressing WT or Y142F β-catenin but did not interrupt adhesion of L-H1-E-cad, L-E-cad, and MDCK cells expressing the Y489F or Y654F mutant β-catenins. PAR-2 activation decreased the TER of monolayers of MDCK cells expressing WT or Y142F β-catenin 40–45%. However, PAR-2 activation did not decrease the TER of monolayers of MDCK cells expressing Y489F or Y654F β-catenin. The protein tyrosine phosphatase PTP1B binds to the cadherin cytoplasmic domain and dephosphorylates β-catenin. Inhibition of PTP1B interrupted adhesion to E-cadherin-Fc of MDCK cells expressing WT β-catenin but did not affect the adhesion of MDCK cells expressing Y489F or Y654F β-catenin. Similarly, inhibition of PTP1B compromised the TER of MDCK cells expressing WT β-catenin but did not affect the TER of MDCK cells expressing Y489F or Y654F β-catenin. We conclude that phosphorylation of tyrosines 489 and 654 in β-catenin is a necessary step in the process by which G protein-coupled H1 and PAR-2 receptors interrupt E-cadherin adhesion. We also conclude that activation of PAR-2 has no effect on the TER without first interrupting E-cadherin adhesion.

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