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Distribution, physiology and pharmacology of relaxin‐3/RXFP3 systems in brain

Relaxin‐3 is a member of a superfamily of structurally‐related peptides that includes relaxin and insulin‐like peptide hormones. Soon after the discovery of the relaxin‐3 gene, relaxin‐3 was identified as an abundant neuropeptide in brain with a distinctive topographical distribution within a small number of GABAergic neuron populations that is well conserved across species. Relaxin‐3 is thought to exert its biological actions through a single class‐A GPCR – relaxin‐family peptide receptor 3 (RXFP3). Class‐A comprises GPCRs for relaxin‐3 and insulin‐like peptide‐5 and other peptides such as orexin and the monoamine transmitters. The RXFP3 receptor is selectively activated by relaxin‐3, whereas insulin‐like peptide‐5 is the cognate ligand for the related RXFP4 receptor. Anatomical and pharmacological evidence obtained over the last decade supports a function of relaxin‐3/RXFP3 systems in modulating responses to stress, anxiety‐related and motivated behaviours, circadian rhythms, and learning and memory. Electrophysiological studies have identified the ability of RXFP3 agonists to directly hyperpolarise thalamic neurons in vitro, but there are no reports of direct cell signalling effects in vivo. This article provides an overview of earlier studies and highlights more recent research that implicates relaxin‐3/RXFP3 neural network signalling in the integration of arousal, motivation, emotion and related cognition, and that has begun to identify the associated neural substrates and mechanisms. Future research directions to better elucidate the connectivity and function of different relaxin‐3 neuron populations and their RXFP3‐positive target neurons in major experimental species and humans are also identified.