Activation of Adhesion G Protein-coupled Receptors

Abstract

Members of the adhesion G protein-coupled receptor (aGPCR) family carry an agonistic sequence within their large ectodomains. Peptides derived from this region, called the sequence, can activate the respective receptor. As the conserved core region of the sequence is highly similar between aGPCRs, the agonist specificity of sequence-derived peptides was tested between family members using cell culture-based second messenger assays. peptides derived from aGPCRs of subfamily VI (GPR110/ADGRF1, GPR116/ADGRF5) and subfamily VIII (GPR64/ADGRG2, GPR126/ADGRG6) are able to activate more than one member of the respective subfamily supporting their evolutionary relationship and defining them as pharmacological receptor subtypes. Extended functional analyses of the sequences and derived peptides revealed agonist promiscuity, not only within, but also between aGPCR subfamilies. For example, the-derived peptide of GPR110 (subfamily VI) can activate GPR64 and GPR126 (both subfamily VIII). Our results indicate that key residues in the sequence are very similar between aGPCRs allowing for agonist promiscuity of several-derived peptides. Therefore, aGPCRs appear to be pharmacologically more closely related than previously thought. Our findings have direct implications for many aGPCR studies, as potential functional overlap has to be considered for and studies. However, it also offers the possibility of a broader use of more potent peptides when the original sequence is less effective.

A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1

“…Several aGPCRs besides rat LPHN1 and its homologs in C. elegans and Drosophila , including GPR126, GPR133, GPR64, GPR114, GPR56, GPR110, and GPR116, have been reported to be activated by their Stachel peptide, which functions as a tethered agonist ( Demberg et al., 2015 , Demberg et al., 2017 , Kishore et al., 2016 , Liebscher et al., 2014 , Muller et al., 2015 , Scholz et al., 2017 , Stoveken et al., 2015 ) ( Figures 2 A and 2B). Recent studies showed that addition of the synthesized Stachel peptide on full-length receptors in trans activated the receptors ( Liebscher et al., 2014 , Stoveken et al., 2015 ).…”

Trendbericht Biochemie Teil 3: Adhäsions‐GPCR ‐‐ Hindernisse und Perspektiven

“…Jedoch ist der Einsatz im endogenen Expressionssystem nicht besonders zielgerichtet, da ho-he Konzentrationen und Lösungsmittelzusatz erforderlich sind. 22) Die aGPCR-Forschung sucht daher nach wie vor nach kleinmolekularen Agonisten und Antagonisten. Breit angelegte Screenings lieferten bereits erste agonistische und antagonistische Substanzen, die jedoch noch nicht rezeptorspezifisch sind.…”

Excessive Extracellular ATP Desensitizes P2Y2 and P2X4 ATP Receptors Provoking Surfactant Impairment Ending in Ventilation-Induced Lung Injury

“…GPR116 is also known as Ig-Hepta which has Ig-like repeats in the N-terminal extracellular domain and is highly expressed in the lung [ 64 ]. GPR116 is thought to be an orphan GPCR carrying an agonistic protein sequence ( Stachel sequence) that functions as a tethered agonist after the removal or a structural change of the N-terminal from the C-terminal fragment of the Stachel sequence [ 77 ]. Recently, the activation of the GPR116 by synthetic peptides resembling the C-terminal fragment has been reported [ 77 ].…”

“…GPR116 is thought to be an orphan GPCR carrying an agonistic protein sequence ( Stachel sequence) that functions as a tethered agonist after the removal or a structural change of the N-terminal from the C-terminal fragment of the Stachel sequence [ 77 ]. Recently, the activation of the GPR116 by synthetic peptides resembling the C-terminal fragment has been reported [ 77 ]. In addition, SP-D may function as a ligand activating the GPR116 [ 64 ].…”