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Resolving the Unconventional Mechanisms Underlying RXFP1 and RXFP2 Receptor Function
Author(s) -
Hartley Brigham J.,
Scott Daniel J.,
Callander Gabrielle E.,
Wilkinson Tracey N.,
Ganella Despina E.,
Kong Chze K.,
Layfield Sharon,
Ferraro Tania,
Petrie Emma J.,
Bathgate Ross A. D.
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.03949.x
Subject(s) - g protein coupled receptor , relaxin , rhodopsin like receptors , receptor , ectodomain , microbiology and biotechnology , chemistry , ligand (biochemistry) , biochemistry , biology , metabotropic receptor , agonist
The receptors for relaxin and insulin‐like peptide 3 (INSL3) are now well‐characterized as the relaxin family peptide (RXFP) receptors RXFP1 and RXFP2, respectively. They are G‐protein‐coupled receptors (GPCRs) with closest similarity to the glycoprotein hormone receptors, with both containing large ectodomains with 10 leucine‐rich repeats (LRRs). Additionally, RXFP1 and RXFP2 are unique in the LGR family in that they contain a low‐density lipoprotein class A (LDL‐A) module at their N‐terminus. Ligand‐mediated activation of RXFP1 and RXFP2 is a complex process involving various domains of the receptors. Primary ligand binding occurs via interactions between B‐chain residues of the peptides with specific residues in the LRRs of the ectodomain. There is a secondary binding site in the transmembrane exoloops which may interact with the A chain of the peptides. Receptor signaling through cAMP then requires the unique LDL‐A module, as receptors without this domain bind ligand normally but do not signal. This is an unconventional mode of activation for a GPCR, and the precise mode of action of the LDL‐A module is currently unknown. The specific understanding of the mechanisms underlying ligand‐mediated activation of RXFP1 and RXFP2 is crucial in terms of targeting these receptors for future drug development.