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2015 ; 67
(2
): 389-440
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
International Union of Basic and Clinical Pharmacology XCV Recent advances in
the understanding of the pharmacology and biological roles of relaxin family
peptide receptors 1-4, the receptors for relaxin family peptides
#MMPMID25761609
Halls ML
; Bathgate RA
; Sutton SW
; Dschietzig TB
; Summers RJ
Pharmacol Rev
2015[]; 67
(2
): 389-440
PMID25761609
show ga
Relaxin, insulin-like peptide 3 (INSL3), relaxin-3, and INSL5 are the cognate
ligands for the relaxin family peptide (RXFP) receptors 1-4, respectively. RXFP1
activates pleiotropic signaling pathways including the signalosome protein
complex that facilitates high-sensitivity signaling; coupling to G?(s), G?(i),
and G?(o) proteins; interaction with glucocorticoid receptors; and the formation
of hetero-oligomers with distinctive pharmacological properties. In addition to
relaxin-related ligands, RXFP1 is activated by Clq-tumor necrosis factor-related
protein 8 and by small-molecular-weight agonists, such as ML290
[2-isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide],
that act allosterically. RXFP2 activates only the G?(s)- and G?(o)-coupled
pathways. Relaxin-3 is primarily a neuropeptide, and its cognate receptor RXFP3
is a target for the treatment of depression, anxiety, and autism. A variety of
peptide agonists, antagonists, biased agonists, and an allosteric modulator
target RXFP3. Both RXFP3 and the related RXFP4 couple to G?(i)/G?(o) proteins.
INSL5 has the properties of an incretin; it is secreted from the gut and is
orexigenic. The expression of RXFP4 in gut, adipose tissue, and ?-islets together
with compromised glucose tolerance in INSL5 or RXFP4 knockout mice suggests a
metabolic role. This review focuses on the many advances in our understanding of
RXFP receptors in the last 5 years, their signal transduction mechanisms, the
development of novel compounds that target RXFP1-4, the challenges facing the
field, and current prospects for new therapeutics.