Relaxin Family Peptides and Receptors in Mammalian Brain

Abstract

As a foundation for regulatory and functional studies of central relaxin family peptide receptor systems, we are mapping the distribution of the different receptors in the brain of rat, mouse, and nonhuman primates, attempting to identify the nature of the receptor-positive neurons in key circuits and establish the complementary distribution of the respective ligands in these species. Here we review progress in mapping RXFP1, RXFP2, and RXFP3 (mRNAs and proteins) and their respective ligands and discuss some of the putative functions for these peptides and receptors that are being explored using receptor-selective agonist and antagonist peptides and receptor and peptide gene deletion mouse strains. Comparative studies reveal an association of RXFP1 and RXFP2 with excitatory neurons but a differential regional or cellular distribution, in contrast to the association of RXFP3 with inhibitory neurons. These studies also reveal differences in the distribution of RXFP1 and RXFP2 in rat and mouse brain, whereas the distribution of RXFP3 is more conserved across these species. Enrichment of RXFP1/2/3 in olfactory, cortical, thalamic, limbic, hypothalamic, midbrain, and pontine circuits suggests a diverse range of modulatory actions for these receptors. For example, experimental evidence in the rat reveals that RXFP1 activation in the amygdala inhibits memory consolidation, RXFP2 activation in striatum produces sniffing behavior, and RXFP3 modulation has effects on feeding and metabolism, the activity of the septohippocampal pathway, and spatial memory. Further studies are now required to reveal additional details of these and other functions linked to relaxin family peptide receptor signaling in mammalian brain and the precise mechanisms involved.

Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats

“…Thus both anatomical and physiological evidence supports a pathway, whereby circulating RLX results in activation of neurons in the SFO with subsequent neuroendocrine and autonomic effects mediated by projections to structures within the blood-brain barrier, such as the PVN and SON (4). Relatively little is known about the function of CNS RXFP1 receptors inside the blood-brain barrier, although it has been suggested that RLX peptide systems within the brain may subserve a local neuromodulatory function (21).…”

“…The decrease in plasma osmolality and osmotic threshold for AVP secretion normally seen in the first half of pregnancy occurs simultaneous to increased plasma RLX (52), and a decrease in osmolality does not occur in ovariectomized or RLX-immunoneutralized P rats (38). Immunoneutralization of RLX (icv) in the second half of rat pregnancy (days [12][13][14][15][16][17][18][19][20][21][22] blocks the increase in water consumption that is normally mediated by an effect of RLX in the forebrain at this time (58).…”

“…RLX-2 in humans is functionally equivalent to RLX-1 in all other mammals, and often both are called simply "relaxin" (2,4,21). Although best known for its role in growth and remodeling of the female reproductive tract during pregnancy, RLX peptide and RLX binding sites are present in male reproductive tissue and the heart, vasculature, kidney, and brain of both males and females.…”

Synthesis of fluorescent analogs of relaxin family peptides and their preliminary in vitro and in vivo characterization

“…For example, in situ hybridization (Piccenna et al, 2005) and radioligand binding studies (Ma et al, 2006) have revealed that RXFP1 mRNA/binding sites are broadly distributed within the rodent brain including high densities in the olfactory bulb, cortex, hippocampus and subiculum, amygdala, circumventricular organs, thalamus, hypothalamus, and brainstem (Ma and Gundlach, 2007; Gundlach et al, 2009). This broad distribution suggests that relaxin/RXFP1 signaling modulates a diverse range of neural circuits, although the nature of this modulation and the relative role of endogenously/locally produced relaxin vs. any effects of circulating relaxin are not known.…”

Partial agonist activity of R3(BΔ23–27)R/I5 at RXFP3 – Investigation of in vivo and in vitro pharmacology

“…Potential roles in appetite regulation, stress response, as well as memory and learning have been described (Tanaka et al, 2005;Nunez et al, 2006;Gundlach et al, 2009). The expression of relaxin-3 is restricted to the central nervous system, while the receptor RXFP3 besides brain is also expressed at low levels in most peripheral organs analysed, but the function of the receptor in peripheral organs is not known.…”