Activation of Adhesion G Protein-coupled Receptors: AGONIST SPECIFICITY OF STACHEL SEQUENCE-DERIVED PEPTIDES.

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.