The GPCR superfamily is indisputably the largest gene family in the human genome, containing approximately 800 members grouped into five main families, according to the GRAFS classification system. Recent elucidation of their activation mechanism makes the adhesion of G protein-coupled receptors (aGPCR) one of the most interesting targets for GPCR specialists to study.
Many aGPCRs are still orphan receptors and work is underway to deorphanize them, including full characterization of their downstream signaling pathways. Adhesion GPCRs get their name from their large N-terminal domain that has adhesion-like domains such as EGF. Their mode of activation remained obscure until the identification of a tethered-agonist peptide sequence, Stachel, in their extended extracellular region.
aGPCR activation is driven by a self-proteolytic process that cleaves the large ectododomain and makes the Stachel sequence accessible to act as an intrinsic agonist and to trigger downstream events.
Using either synthetic peptides derived from Stachel sequences, transfected cells, or ex-vivo models (lung tissue or cells from renal papilla), Lilian Demberg illustrates how aGPCR could activate either Gs or Gq signaling pathways.
Due to the high sequence homology of the Stachel peptide sequence among aGPCRs, Demberg also demonstrates that cross-activation occurs between members of different aGPCR groups, leading to complex activation or dual coupling of downstream GS/Gq effectors.
Although GPCRs have been studied for decades, their complex biology is far from being fully elucidated. They are an inexhaustible source of inspiration for research in this field and most certainly represent future Nobel prize opportunities for GPCR specialists.
It's worth a try…
Lilian M. Demberg et al.
Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany
Journal of Biomological Chemistry, 2017 March 17; 292(11):4383-4394.
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 Stachel sequence, can activate the respective receptor. As the conserved core region of the Stachel sequence is highly similar between aGPCRs, the agonist specificity of Stachel sequence-derived peptides was tested between family members using cell culture-based second messenger assays. Stachel 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 Stachel sequences and derived peptides revealed agonist promiscuity, not only within, but also between aGPCR subfamilies. For example, the Stachel-derived peptide of GPR110 (subfamily VI) can activate GPR64 and GPR126 (both subfamily VIII). Our results indicate that key residues in the Stachel sequence are very similar between aGPCRs allowing for agonist promiscuity of several Stachel-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 in vitro and in vivo studies. However, it also offers the possibility of a broader use of more potent peptides when the original Stachel sequence is less effective.