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Relaxin-3 is a neuropeptide that was discovered in 2001,^[1] and which is highly conserved in species ranging from flies, fish, rodents and humans.^[2] Relaxin-3 is a member and ancestral gene of the relaxin family of peptides, which includes the namesake hormone relaxin (designated 'H2 relaxin' in humans) which mediates peripheral actions during pregnancy and which was found to relax the pelvic ligament in guinea pigs almost a century ago. The cognate receptor for relaxin-3 is the G-protein coupled receptor RXFP3 (relaxin family peptide 3 receptor), however relaxin-3 is pharmacologically able to also cross react with RXFP1 and RXFP3 (although the physiological relevance of such interactions, if they exist endogenously, are currently unknown).

Structure

Relaxin-3 consists of 51 amino acids in humans which are arranged into a two-chain structure (designated the A-chain and B-chain). There are three disulfide bonds (two interchain, one intrachain), with the residues that mediate binding to/activation of RXFP3 residing within the B-chain. At translation, pro-relaxin-3 also contains a C-chain (in between the A and B-chains) which is removed via protolytic cleavage to form the mature neuropeptide.^[3]

Distribution

Relaxin-3 is mostly expressed within neurons of the brain, where it is packaged into dense cored vesicles and trafficked along axons where it can be detected in presynaptic vesicles before release onto target neurons, characteristic of a neurotransmitter.^[4] The largest number of relaxin-3-positive neurons in the rodent brain are within a region of the pontine brainstem known as the nucleus incertus,^[5] while smaller populations are present within the pontine raphe, periaqueductal grey, and an area dorsal to the substantia nigra. From these centres, relaxin-3 innervates a broad range of brain regions which are also rich in RXFP3 mRNA/binding sites, including the extended limbic system and the septohippocampal pathway.^[6]^[7]

Function

The broad distribution of relaxin-3 fibres/RXFP3 within several key neuronal circuits suggests an ability to modulate a broad range of behaviours. This has been confirmed in a growing number of rodent studies, which demonstrate relaxin-3 is able to modulate arousal, the response to stress, feeding/metabolism and memory; and likely plays a role in the generation/regulation of hippocampal theta rhythm.^[8]

Relevance to human disease

Neuropeptides such as relaxin-3 are attracting increasing interest as targets for the pharmacological treatment of a range of neuropsychiatric diseases. Due to the ability of relaxin-3 to modulate neuronal processes/behaviours such as mood, stress responses and cognition, which are often aberrant in mental illnesses, considerable potential exists for the development of relaxin-3-based drugs to therapeutically treat depression and other mental illnesses.

References

^ Bathgate, Ross A; Samuel CS; Burazin TC; Layfield S; Claasz AA; Reytomas IG; Dawson NF; Zhao C; Bond C; Summers RJ; Parry LJ; Wade JD; Tregear GW (11 Jan 2002). "Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family". The Journal of Biological Chemistry. 277 (2): 1148–57. doi:10.1074/jbc.m107882200. PMID 11689565.
^ Wilkinson, Tracy N; Speed TP; Tregear GW; Bathgate RA (12 Feb 2005). "Evolution of the relaxin-like peptide family". BMC Evolutionary Biology. 5 (1): 15. doi:10.1186/1471-2148-5-14. PMC 551602. PMID 15707501.
^ Rosengren, Johan K; Lin F; Bathgate RA; Tregear GW; Daly NL; Wade JD; Craik DJ (3 March 2006). "Solution structure and novel insights into the determinants of the receptor specificity of human relaxin-3". The Journal of Biological Chemistry. 281 (9): 5845–51. doi:10.1074/jbc.m511210200. PMID 16365033.
^ Tanaka, M; Iijima N; Miyamoto Y; Fukusumi S; Itoh Y; Ozawa H; Ibata Y (March 2005). "Neurons expressing relaxin 3/INSL 7 in the nucleus incertus respond to stress". The European Journal of Neuroscience. 21 (6): 1659–70. doi:10.1111/j.1460-9568.2005.03980.x. PMID 15845093. S2CID 24594286.
^ Ryan, Phil J; Ma S; Olucha-Bordonau FE; Gundlach AL (May 2011). "Nucleus incertus--an emerging modulatory role in arousal, stress and memory". Neuroscience & Biobehavioral Reviews. 35 (6): 1326–41. doi:10.1016/j.neubiorev.2011.02.004. PMID 21329721. S2CID 24464719.
^ Smith, Craig M; Shen PJ; Banerjee A; Bonaventure P; Ma S; Bathgate RA; Sutton SW; Gundlach AL (1 Oct 2010). "Distribution of relaxin-3 and RXFP3 within arousal, stress, affective and cognitive circuits of mouse brain". Journal of Comparative Neurology. 518 (19): 4016–45. doi:10.1002/cne.22442. PMID 20737598. S2CID 11971485.
^ Ma, Sherie; Bonaventure P; Ferraro T; Shen PJ; Burazin TC; Bathgate RA; Liu C; Tregear GW; Sutton SW; Gundlach AL (5 Jan 2007). "Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled reveptor-135 in the rat". Neuroscience. 144 (1): 165–90. doi:10.1016/j.neuroscience.2006.08.072. PMID 17071007. S2CID 42656023.
^ Smith, Craig; Ryan P; Hosken I; Ma S; Gundlach A (December 2011). "Relaxin-3 systems in the brain--the first 10 years". Journal of Chemical Neuroanatomy. 42 (4): 262–275. doi:10.1016/j.jchemneu.2011.05.013. PMID 21693186. S2CID 9589579.