Abstract
RXFP3 (relaxin-family peptide 3 receptor) is the cognate G-protein-coupled receptor for the neuropeptide, relaxin-3. RXFP3 is expressed widely throughout the brain, including the hypothalamus, where it has been shown to modulate feeding behavior and neuroendocrine activity in rodents. In order to better characterize its potential mechanisms of action, this study determined whether RXFP3 is expressed by dopaminergic neurons within the arcuate nucleus (ARC) and dorsomedial hypothalamus (DMH), in addition to the ventral tegmental area (VTA). Neurons that express RXFP3 were visualized in coronal brain sections from RXFP3-Cre/tdTomato mice, which express the tdTomato fluorophore within RXFP3-positive cells, and dopaminergic neurons in these areas were visualized by simultaneous immunohistochemical detection of tyrosine hydroxylase-immunoreactivity (TH-IR). Approximately 20% of ARC neurons containing TH-IR coexpressed tdTomato fluorescence, suggesting that RXFP3 can influence the dopamine pathway from the ARC to the pituitary gland that controls prolactin release. The ability of prolactin to reduce leptin sensitivity and increase food consumption therefore represents a potential mechanism by which RXFP3 activation influences feeding. A similar proportion of DMH neurons containing TH-IR expressed RXFP3-related tdTomato fluorescence, consistent with a possible RXFP3-mediated regulation of stress and neuroendocrine circuits. In contrast, RXFP3 was barely detected within the VTA. TdTomato signal was absent from the ARC and DMH in sections from Rosa26-tdTomato mice, suggesting that the cells identified in RXFP3-Cre/tdTomato mice expressed authentic RXFP3-related tdTomato fluorescence. Together, these findings identify potential hypothalamic mechanisms through which RXFP3 influences neuroendocrine control of metabolism, and further highlight the therapeutic potential of targeting RXFP3 in feeding-related disorders.
Highlights
Relaxin-family peptide 3 receptor (RXFP3) is a G-proteincoupled receptor that is primarily expressed in the brain, and is activated by its cognate neuropeptide, relaxin-3 (Ma et al, 2017)
In situ hybridisation data from the Allen Brain Atlas (Lein et al, 2007) demonstrates that tyrosine hydroxylase (TH) mRNA is highly expressed within the arcuate nucleus (ARC) (Figures 1A,B), and a similar distribution of neurons containing tyrosine hydroxylase-immunoreactivity (TH-IR) was observed in RXFP3-Cre/tdTomato mice (Figure 1C)
That RXFP3 activation inhibits this small proportion of ARC dopaminergic neurons, as electrophysiological studies suggest that postsynaptic RXFP3 signaling is predominantly inhibitory in rat and mouse (Kania et al, 2017; Ch’ng et al, 2019; Kania et al, 2020)
Summary
Relaxin-family peptide 3 receptor (RXFP3) is a G-proteincoupled receptor that is primarily expressed in the brain, and is activated by its cognate neuropeptide, relaxin-3 (Ma et al, 2017). As exogenous relaxin-3 pharmacologically cross-reacts with RXFP1, the preferred receptor for the hormone relaxin (HaugaardKedstrom et al, 2011), selective RXFP3 agonists and antagonists have been developed that provide more selective pharmacological modulation of RXFP3 (Ganella et al, 2012, 2013; Shabanpoor et al, 2012; Smith et al, 2014; De Ávila et al, 2018; Lee et al, 2020). RXFP3 agonists are not orexigenic in mice (Smith et al, 2013; Grosse et al, 2014), ICV administration of a selective RXFP3 antagonist has anorexigenic effects in this species, highlighting a role of endogenous relaxin-3/RXFP3 in feeding (Smith et al, 2014)
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