Relaxin family peptide systems and the central nervous system

Abstract

Since its discovery in the 1920s, relaxin has enjoyed a reputation as a peptide hormone of pregnancy. However, relaxin and other relaxin family peptides are now associated with numerous non-reproductive physiologies and disease states. The new millennium bought with it the sequence of the human genome and subsequently new directions for relaxin research. In 2002, the ancestral relaxin gene RLN3 was identified from genome databases. The relaxin-3 peptide is highly expressed in a small region of the brain and in species from teleost to primates and has both conserved sequence and sites of expression. Combined with the discovery of the relaxin family peptide receptors, interest in the role of the relaxin family peptides in the central nervous system has been reignited. This review explores the relaxin family peptides that are expressed in or act upon the brain, the receptors that mediate their actions, and what is currently known of their functions.

Fig. 1

Distribution of RXFP2, as reflected by [¹²⁵I]-INSL3-binding sites, in coronal sections of adult rat forebrain. a–n Representative autoradiographs illustrating the pattern of specific [¹²⁵I]-INSL3-binding sites throughout the rostrocaudal extent of the rat forebrain. m′ 100 nM unlabeled INSL3 was added to the slides to demonstrate the specificity of the [¹²⁵I]-INSL3-binding (NSB). Scale bar 1 mm. Acb accumbens nucleus (n), APir amygdalopiriform transition area, BL basolateral amygdaloid n, CPu caudate putamen, fr fasciculus retroflexus, DMD dorsomedial hypothalamic n, ICj islands of Calleja, IPAC interstitial n of posterior limb of anterior commissure, IPN interpeduncular n, LD laterodorsal thalamic n, LOT n of lateral olfactory tract, LP lateral posterior thalamic n, LPB lateral parabrachial n, LSS lateral stripe of striatum, M1 primary motor cortex, M2 secondary motor cortex, MD mediodorsal thalamic n, mHb medial habenular n, PaA parietal cortex, anterior area, Pf parafascicular thalamic n, Po posterior thalamic nuclear group, Rt reticular thalamic n, S subiculum, S1 primary somatosensory cortex, S1BF primary somatosensory cortex, barrel field, VEn ventral endopiriform n, VL ventrolateral thalamic n, VLG ventrolateral geniculate n, VLS ventrolateral striatum, VM secondary visual cortex, medial (adapted from [51] with permission, copyright Elsevier 2009)

Fig. 2

Comparative distribution of (a–b) RXFP1 (LGR7) mRNA and (a′–b′) [³³P]-labeled human relaxin-binding sites in coronal sections of adult rat brain. Arc arcuate hypothalamic n, BLA basolateral amygdala, CA3 field of hippocampus, CL centrolateral thalamic n, CM centromedial thalamic n, DG dentate gyrus of hippocampus, MO motor cortex, 1, 5, 6b layers of cerebral cortex, PC paracentral thalamic n, PV paraventricular thalamic n, PVN paraventricular nucleus (n), REm reuniens thalamic n medial, SFO subfornical organ, SO supraoptic nucleus, VIS visual cortex (from [61] with permission, copyright Elsevier 2009)

Fig. 3

Circulating relaxin acts on subfornical organ (SFO) neurons to stimulate water drinking in rats. Water intake during 90 min following i.v. infusion of human relaxin for 1 h in normal rats or rats with ablation of the SFO, OVLT, parts of the SFO, or tissue adjacent to these regions, or sham lesions. Mean and SEM are shown, and number of rats in each group are given in parentheses. Control, normal rats; SHAMX, sham lesions; SFOX, >90% of SFO ablated; SFO >50×, 50–90% of SFO ablated; SFO <50×, <50% of SFO ablated; SFOML, lesion missed SFO and damaged adjacent tissue; OVLTX, >90% of OVLT ablated; OVLTMX, lesion missed OVLT and ablated tissue in the adjacent regions. *p < 0.05 versus control group (from [72] with permission)

Fig. 4

The distribution of relaxin-3 immunoreactivity in the rat brain. a, b Representative confocal micrographs in coronal sections through the nucleus incertus (NI). b High-resolution image reveals staining in the cytoplasm of cells. 4V fourth ventricle, mlf medial longitudinal fasciculus, NIc nucleus incertus pars compacta, NId nucleus incertus pars dissiparta, PDTg posterodorsal tegmental nucleus. Scale bars 200 μm (a) and 50 μm (b)

Fig. 5

The effect of repeat forced swim (RFS) on relaxin-3 mRNA and hnRNA in the rat nucleus incertus (NI) in the presence or absence of the CRF-R1 antagonist antalarmin. a, b Representative thionin-stained sections used to detect RLX3 mRNA in vehicle- and antalarmin-injected rats at 0.5 h after RFS and a′, b′ corresponding high-power, darkfield digital micrographs of the NI in these sections. c, d Semi-quantitative analysis of the effects of antalarmin on (c) RLX3 mRNA and (d) hnRNA expression following RFS. Values are mean ± SEM, n = 4/group. RLX3 mRNA *p < 0.05 versus control, ^† p < 0.05 versus antalarmin-treated; and RLX3 hnRNA *p < 0.05 versus control, ^† p < 0.05 versus antalarmin-treated. Scale bars, 150 mm (a, b) 40 mm (a′, b′) (from [91] with permission, copyright Elsevier 2009)

Fig. 6

The effect of chronic relaxin-3 administration on food intake and plasma TSH in rats. a Cumulative food intake after repeated intra-paraventricular nucleus (iPVN) administration of vehicle (white circles), human relaxin-3 (H3) in ad libitum fed rats (plus sign) or H3 in pair-fed (PF; black triangle) rats for 7 days. b Effect of repeated iPVN administration of vehicle, H3 in ad libitum-fed rats or H3 in pair-fed (H3PF) for 7 days on plasma TSH. *p < 0.05 versus vehicle, n = 8–11 (from [94] with permission, copyright Elsevier 2009)

Fig. 7

Effects of RXFP3-specific agonist (R3/I5) and/or antagonist (R3(BΔ23–27)R/I5; ΔR3/I5) infusion on spatial working memory performance assessed in the spontaneous alternation task (SAT). Artificial cerebrospinal fluid (aCSF) vehicle or different concentrations of peptides (ng) were infused into the medial septum of rats 10 min prior to the SAT. Numbers of rats in each group (n = 6–9) are indicated in brackets within the bars on the figures (from [99] with permission, copyright 2009)