Relaxin family peptide

Overview: Relaxin family peptide receptors (RXFP, nomenclature as approved by the NC-IUPHAR committee on relaxin family peptide receptors, Bathgate et al. 2006) may be divided into two groups RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are a number of heterodimeric peptide hormones analogous to insulin: H1 relaxin [ENSG00000107018], H2 relaxin [ENSG00000107014], H3 relaxin [also known as INSL7, ENSG00000171136], insulin-like peptide (INSL) 3 [OTTHUMG00000070952*] and INSL5 [ENSG00000172410].

Species homologues of relaxin have distinct pharmacology – H2 relaxin interacts with RXFP1 and RXFP2, mouse and rat relaxin selectively bind to and activate RXFP1 (Scott et al., 2005a) and porcine relaxin may have a higher efficacy than H2 relaxin (Halls et al., 2005). H3 relaxin has differential affinity for RXFP2 receptors between species; mouse and rat RXFP2 have a higher affinity for H3 relaxin (Scott et al., 2005b). At least two binding sites have been identified on the RXFP1 and RXFP2 receptors: a high-affinity site in the leucine-rich repeat region of the ectodomain and a somewhat lower-affinity site located in the surface loops of the transmembrane (Sudo et al., 2003; Halls et al., 2005). The unique N-terminal LDLa module of RXFP1 and RXFP2 is essential for receptor signalling (Scott et al., 2006).

Nomenclature	RXFP1	RXFP2
Other names	Relaxin receptor, LGR7, leucine-rich repeat-containing G protein-coupled receptor 7, RX1	INSL3 receptor, LGR8, leucine-rich repeat-containing G protein-coupled receptor 8, GREAT, RX2
Ensembl ID	ENSG00000171509	ENSG00000133105
Principal transduction	Gs, GαoB, Gαι3 (Hsu et al., 2002; Halls et al., 2006; 2009a;)	Gs, GαoB (Kumagai et al., 2002; Halls et al., 2006)
Rank order of potency	H2 relaxin > H3 relaxin >> INSL3 (Sudo et al., 2003)	INSL3 > H2 relaxin >> H3 relaxin (Kumagai et al., 2002; Sudo et al., 2003)
Antagonists	LGR7-truncate (Scott et al., 2006)	INSL3 B-chain analogue (Del Borgo et al., 2006), (des 1-8) A-chain INSL3 analogue (Bullesbach and Schwabe, 2005)
Probes	[33P]-H2 relaxin (0.2 nM, Sudo et al., 2003), europium-labelled H2 relaxin (1 nM; Hossain et al., 2009)	[33P]-H2 relaxin (1.06 nM; Sudo et al., 2003), [125I]-INSL3 (0.1 nM; Muda et al., 2005), europium-labelled INSL3 (0.9 nM; Shabanpoor et al., 2008)

Mutations in INSL3 and LGR8 (RXFP2) have been reported in populations of patients with cryptorchidism (Ferlin et al., 2003). Numerous splice variants of the human RXFP1 and RXFP2 receptors have been identified, none of which bind relaxin family peptides (Muda et al., 2005). Splice variants of RXFP1 encoding the N-terminal LDLa module act as antagonists of RXFP1 signalling (Scott et al., 2005b; 2006;). cAMP elevation appears to be the major signalling pathway for RXFP1 and RXFP2 (Hsu et al., 2000; 2002;), but RXFP1 also activates MAP kinases, nitric oxide signalling and interacts with tyrosine kinases and glucocorticoid receptors (Halls et al., 2007). RXFP1 signalling involves lipid rafts, residues in the C-terminus of the receptor and activation of phosphatidylinositol-3-kinase (Halls et al., 2009a). The pattern of cAMP signalling observed is highly dependent on the cell type in which RXFP1 is expressed (Halls et al., 2009b).

Nomenclature	RXFP3	RXFP4
Other names	Relaxin 3 receptor, GPCR135, somatostatin and angiotensin-like peptide receptor SALPR, RX3	INSL5 receptor, GPCR142, GPR100, relaxin 3 receptor 2, RX4
Ensembl ID	ENSG00000182631	ENSG00000173080
Principal transduction	Gi/o (Matsumoto et al., 2000); van der Westhuizen et al., 2007)	Gi/o (Liu et al., 2003b)
Rank order of potency	H3 relaxin > H3 relaxin B chain (Liu et al., 2003a)	INSL5 = H3 relaxin > H3 relaxin B chain (Liu et al., 2003b; 2005a;)
Antagonists	INSL5 (Liu et al., 2005a), R3(BΔ23-27)R/I5 chimeric peptide (Kuei et al., 2007)	R3(BΔ23-27)R/I5 chimeric peptide (Kuei et al., 2007)
Probes	[125I]-H3 relaxin (0.3 nM; Liu et al., 2003a), [125I]-H3-B/INSL5 A chimera (0.5 nM; Liu et al., 2005b)	[125I]-H3 relaxin (0.2 nM; Liu et al., 2003b), [125I]-H3-B/INSL5 A chimera (1.2 nM; Liu et al., 2005b)

H3 relaxin acts as an agonist at both RXFP3 and RXFP4 whereas INSL5 is an agonist at RXFP4 and an antagonist at RXFP3. Unlike RXFP1 and RXFP2 both RXFP3 and RXFP4 are encoded by a single exon and therefore no splice variants exist. The rat RXFP3 sequence has two potential start codons that encode RXFP3L and RXFP3S with the longer variant having an additional 7 amino-acids at the N-terminus. It is not known which variant is expressed. Rat and dog RXFP4 sequences are pseudogenes (Wilkinson et al., 2005). Recent studies suggest that H2 relaxin can interact with RXFP3 at a binding site distinct from that identified by H3 relaxin or analogues, and that this interaction activates pathways distinct from those activated by H3 relaxin (Summers et al., 2009)

Glossary

Abbreviations:

H2 relaxin

human gene 2 relaxin

H3 relaxin

human gene 3 relaxin

INSL3

insulin-like peptide 3

INSL5

insulin-like peptide 5

Further Reading

Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ (2006). International Union of Pharmacology LVII: Recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev58: 7–31.

Bathgate RAD, Hsueh AJW, Sherwood OD (2005). Physiology and molecular biology of the relaxin peptide family. In: Neill JD (ed.). Knobil and Neill's Physiology of Reproduction, third edition. Academic Press: New York, pp. 679–768.

Dschietzig T, Bartsch C, Baumann G, Stangl K (2006). Relaxin-a pleiotropic hormone and its emerging role for experimental and clinical therapeutics. Pharmacol Ther112: 38–56.

Halls ML, van der Westhuizen ET, Bathgate RA, Summers RJ (2007). Relaxin family peptide receptors – former orphans reunite with their parent ligands to activate multiple signalling pathways. Br J Pharmacol150: 677–691.

Samuel CS, Du XJ, Bathgate RA, Summers RJ (2006). ‘Relaxin’ the stiffened heart and arteries: the therapeutic potential for relaxin in the treatment of cardiovascular disease. Pharmacol Ther112: 529–552.

van der Westhuizen ET, Halls ML, Samuel CS, Bathgate RA, Unemori EN, Sutton SW et al. (2008). Relaxin family peptide receptors – from orphans to therapeutic targets. Drug Discov Today13: 640–651.

van der Westhuizen ET, Summers RJ, Halls ML, Bathgate RA, Sexton PM (2007). Relaxin receptors – new drug targets for multiple disease states. Curr Drug Targets8: 91–104.