Relaxin-3 is aneuropeptide that was discovered in 2001,[1] and which is highly conserved in species ranging fromflies,fish,rodents andhumans.[2] Relaxin-3 is a member and ancestral gene of the relaxin family ofpeptides, which includes the namesake hormonerelaxin (designated 'H2 relaxin' in humans) which mediates peripheral actions during pregnancy and which was found to relax thepelvic ligament in guinea pigs almost a century ago. The cognate receptor for relaxin-3 is the G-protein coupled receptorRXFP3 (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 existendogenously, are currently unknown).
Relaxin-3 consists of 51amino acids in humans which are arranged into a two-chain structure (designated the A-chain and B-chain). There are threedisulfide 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]
Relaxin-3 is mostly expressed withinneurons of the brain, where it is packaged into dense cored vesicles and trafficked alongaxons where it can be detected inpresynaptic vesicles before release onto target neurons, characteristic of aneurotransmitter.[4] The largest number of relaxin-3-positive neurons in the rodent brain are within a region of the pontine brainstem known as thenucleus incertus,[5] while smaller populations are present within the pontine raphe, periaqueductal grey, and an area dorsal to thesubstantia nigra. From these centres, relaxin-3 innervates a broad range of brain regions which are also rich in RXFP3 mRNA/binding sites, including the extendedlimbic system and the septohippocampal pathway.[6][7]
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 ofrodent 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 ofhippocampal theta rhythm.[8]
Neuropeptides such as relaxin-3 are attracting increasing interest as targets for the pharmacological treatment of a range ofneuropsychiatric 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.