Relaxin Pathway
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Relaxin Pathway

Relaxin is a two-chain peptide hormone that belongs to the insulin/relaxin peptide family. The relaxin family peptides are limited to the relaxins (H1, H2, and H3) and INSL ( INSL3, INSL4, INSL5, and INSL6). Four G protein-coupled receptors (GPCR) act as the receptors for relaxin family peptides: LGR7 and LGR8 being the receptors for H2 relaxin and INSL3 respectively, and GPCR135 and GPCR142 for H3 relaxin and INSL5, respectively (Ref.1). Relaxin family peptide receptors and their ligands are broadly implicated in the regulation of reproductive and neuroendocrine processes in mammals. Relaxin has many roles in female and male reproduction, as a neuropeptide in the central nervous system, as a vasodilator and cardiac stimulant in the cardiovascular system, and as an antifibrotic agent (Ref.2). Relaxin has been shown to pay a key role within the ovary, being involved in follicle growth, and ovulation. Known sources of Relaxin are the ovary, decidua, placenta, and the prostate. Relaxin is produced in large amounts also by the corpus luteum where it acts as an endocrine hormone positively affecting implantation, placentation and vascularization during the all-important first trimester phase of pregnancy establishment (Ref.3 and4).

The peptide hormone INSL3 and its receptor, RXFP2, have co-evolved alongside relaxin and its receptor, RXFP1. Both RXFP1 and RXFP2 are G protein-coupled receptors (GPCRs) containing the hallmark seven transmembrane helices in addition to a distinct ectodomain of leucine-rich repeats (LRRs) and a single low-density lipoprotein class-A (LDLa) module at the N-terminus. Relaxin binding to RXFP1 induces many cell-specific effects. It is involved in male and female reproduction, inhibits fibroblast proliferation and differentiation, and induces production of matrix metalloproteinases ( MMP 1, 2, 9, 13), producing a collagenolytic effect. Relaxin also influences bone metabolism by inducing osteoclastogenesis and activation of mature osteoclasts through activation of nuclear factor kappa-light-chain-enhancer of activated B cell ( NF-KappaB), Receptor activator of NF-Kappa-B ( RANK), Tartrate-Resistant Acid Phosphatase ( TRAP) and cathepsins (Ref.6). Relaxin- RXFP1, interaction also activate kinase-signaling pathways ( ERK, PI3K, Akt) and gene transcription resulting in activation of the three nitric oxide synthase (NOS) isoforms and production of nitric oxide (NO). Increased NO bioavailability results in vasodilation, increased renal blood flow, increased sodium excretion, and inhibition of TGF-ß-Smad2 signaling. Transcription of vascular endothelial growth factor (VEGF) and matrix metalloproteinases is also stimulated. VEGF further stimulates NO production, and matrix metalloproteinases (MMPs) result in cleavage of big-endothelin-1 to stimulate the endothelin type B receptor, further stimulating NO production via an as yet unspecified NOS isoform and 2) collagen. Overall, these pathways result in improved renal function and reduced renal fibrosis (Ref.7). Both RXFP1 and RXFP2 receptors trigger the 3'–5'-cyclic adenosine monophosphate (cAMP) activation signaling cascade, increase Nitric oxide production, and induce phosphorylation of extracellular signal-regulated kinase ( ERK1/2) (Ref.5 and 6).

Relaxin-3 is a member of the insulin superfamily, which is expressed in the nucleus incertus of the brainstem that has projections to the hypothalamus. Relaxin-3 binds with high affinity to RXFP1 and RXFP3 (Ref.8). Relaxin-3 signaling confers complimentary inhibitory effects to the primary transmitter, as RXFP3 activation is linked to Gi/o and reduces cAMP accumulation. RXFP3 activation also stimulates ERK1/2 MAP kinase and other pathways, although related changes in gene expression or precise roles of RXFP3 signaling within distinct neuronal populations in vivo remain unknown (Ref.9).Insulin-like peptide 5 ( INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5- RXFP4 interaction results in the inhibition of intracellular cAMP levels (Ref.10 and 11). Binding of Relaxin-3 to RXFP4 also caused cellular responses similar to RXFP3, with inhibition of AC, increased GTP-gammaS binding, and increased intracellular calcium when RXFP4 is coexpressed with G-Alpha16 (Ref.2).

Relaxin-induced geometric remodeling has been observed in brain parenchymal arteries, and this remodeling appears to be via the activation of peroxisome proliferator–activated receptor-gamma (Ref.12). The role of Relaxin and its involvement in cancer cell proliferation, metastasis and cell invasion have been proven by numerous studies, further reinforcing its function as a pleiotropic peptide hormone in humans (Ref. 13).