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 theStachelsequence, can activate the respective receptor. As the conserved core region of theStachelsequence is highly similar between aGPCRs, the agonist specificity ofStachelsequence-derived peptides was tested between family members using cell culture-based second messenger assays.Stachelpeptides 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 theStachelsequences and derived peptides revealed agonist promiscuity, not only within, but also between aGPCR subfamilies. For example, theStachel-derived peptide of GPR110 (subfamily VI) can activate GPR64 and GPR126 (both subfamily VIII). Our results indicate that key residues in theStachelsequence are very similar between aGPCRs allowing for agonist promiscuity of severalStachel-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 forin vitroandin vivostudies. However, it also offers the possibility of a broader use of more potent peptides when the originalStachelsequence is less effective.
From the Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry and.
Lilian M
LM
Demberg
From the Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry and.
Jana
J
Winkler
From the Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry and.
Caroline
C
Wilde
From the Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry and.
Kay-Uwe
KU
Simon
From the Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry and.
Julia
J
Schön
the Core Unit Peptide Technologies, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
Sven
S
Rothemund
From the Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry and.
Torsten
T
Schöneberg
From the Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry and simone.proemel@medizin.uni-leipzig.de.
Simone
S
Prömel
From the Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry and ines.liebscher@medizin.uni-leipzig.de.
Ines
0000-0003-4480-8987
I
Liebscher
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002645:Chickens; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010802:Phylogeny; D000072417:Protein Domains; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D010455:Peptides; D043562:Receptors, G-Protein-Coupled
G protein; G protein-coupled receptor (GPCR); NFAT transcription factor; adhesion; cyclic AMP (cAMP); inositol phosphate; peptides; signal transduction