Relaxin-3

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Structure of relaxin-3 Relaxin-3 structure.jpg
Structure of relaxin-3
Relaxin-3 neurons in the mouse nucleus incertus Relaxin3 in the NI.jpg
Relaxin-3 neurons in the mouse nucleus incertus
Distribution of relaxin-3 neurons and projections Distribution of relaxin-3-positive neurons and projections.jpg
Distribution of relaxin-3 neurons and projections

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).

Contents

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.

See also

Related Research Articles

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Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.

Neuropeptide

Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the gut, muscles, and heart.

Neuropeptide Y

Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the mammalian central nervous system, which consists of the brain and spinal cord. It is secreted alongside other neurotransmitters such as GABA and glutamate. 

Vasoactive intestinal peptide Hormone that affects blood pressure / heart rate

Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas, and suprachiasmatic nuclei of the hypothalamus in the brain. VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gallbladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.

Agouti-related peptide

Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene.

Melanin-concentrating hormone (MCH) is a cyclic 19-amino acid orexigenic hypothalamic peptide originally isolated from the pituitary gland of teleost fish, where it controls skin pigmentation. In mammals it is involved in the regulation of feeding behavior, mood, sleep-wake cycle and energy balance.

Relaxin

Relaxin is a protein hormone of about 6000 Da first described in 1926 by Frederick Hisaw.

Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include: alter intrinsic firing activity, increase or decrease voltage-dependent currents, alter synaptic efficacy, increase bursting activity and reconfiguration of synaptic connectivity.

Galanin

Galanin is a neuropeptide encoded by the GAL gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.

Lateral hypothalamus

The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.

Cocaine and amphetamine regulated transcript

Cocaine- and amphetamine-regulated transcript, also known as CART, is a neuropeptide protein that in humans is encoded by the CARTPT gene. CART appears to have roles in reward, feeding, and stress, and it has the functional properties of an endogenous psychostimulant.

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Relaxin/insulin-like family peptide receptor 3

Relaxin/insulin-like family peptide receptor 3, also known as RXFP3, is a human G-protein coupled receptor.

Relaxin/insulin-like family peptide receptor 1

Relaxin/insulin-like family peptide receptor 1, also known as RXFP1, is a human G protein coupled receptor that is one of the relaxin receptors. It is a rhodopsin-like GPCR which is unusual in this class as it contains a large extracellular binding and signalling domain. Some reports suggest that RXFP1 forms homodimers, however the most recent evidence indicates that relaxin binds a non-homodimer of RXFP1.

Relaxin/insulin-like family peptide receptor 4

Relaxin/insulin-like family peptide receptor 4, also known as RXFP4, is a human G-protein coupled receptor.

Relaxin/insulin-like family peptide receptor 2

Relaxin/insulin-like family peptide receptor 2, also known as RXFP2, is a human G-protein coupled receptor.

Neuropeptide S

Neuropeptide S (NPS) is a neuropeptide found in human and mammalian brain, mainly produced by neurons in the amygdala and between Barrington's nucleus and the locus coeruleus, although NPS-responsive neurons extend projections into many other brain areas. NPS binds specifically to a G protein-coupled receptor, NPSR. Animal studies show that NPS suppresses anxiety and appetite, induces wakefulness and hyperactivity, including hyper-sexuality, and plays a significant role in the extinction of conditioned fear. It has also been shown to significantly enhance dopamine activity in the mesolimbic pathway, and inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans.

Nucleus incertus

The nucleus incertus is a region of the rodent pontine brainstem just ventral to the 4th ventricle. The term was coined by George Streeter based on its unknown function at the time, to name a group of cells he observed near the midline of the floor of the 4th ventricle.

Relaxin family peptide hormones Protein family

Relaxin family peptide hormones in humans are represented by 7 members: three relaxin-like (RLN) and four insulin-like (INSL) peptides. This subdivision into 2 classes is based primarily on early findings, and does not reflect the evolutionary origins or physiological differences between peptides. For example, it is known that the genes coding for RLN3 and INSL5 arose from one ancestral gene, and INSL3 shares origin with RLN2 and its multiple duplicates.

References

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.