Abstract
No organ in the body is impervious to the effects of stress, and a coordinated response from all organs is essential to deal with stressors. A dysregulated stress response that fails to bring systems back to homeostasis leads to compromised function and ultimately a diseased state. The components of the corticotropin-releasing factor (CRF) family, an ancient and evolutionarily conserved stress hormone-receptor system, helps both initiate stress responses and bring systems back to homeostasis once the stressors are removed. The mammalian CRF family comprises of four known agonists, CRF and urocortins (UCN1–3), and two known G protein-coupled receptors (GPCRs), CRF1 and CRF2. Evolutionarily, precursors of CRF- and urocortin-like peptides and their receptors were involved in osmoregulation/diuretic functions, in addition to nutrient sensing. Both CRF and UCN1 peptide hormones as well as their receptors appeared after a duplication event nearly 400 million years ago. All four agonists and both CRF receptors show sex-specific changes in expression and/or function, and single nucleotide polymorphisms are associated with a plethora of human diseases. CRF receptors harbor N-terminal cleavable peptide sequences, conferring biased ligand properties. CRF receptors have the ability to heteromerize with each other as well as with other GPCRs. Taken together, CRF receptors and their agonists due to their versatile functional adaptability mediate nuanced responses and are uniquely positioned to orchestrate sex-specific signaling and function in several tissues.
Highlights
The Corticotropin-Releasing Factor and Receptor FamilyCorticotropin-releasing factor/hormone (CRF or CRH), urocortins, their paralogs, urotensin-I and sauvagine, and their two known G protein-coupled receptors, CRF1 and CRF2, are a family of ancient peptide hormones found in all chordates (Figure 1A–C)
Sauvagine, and their two known G protein-coupled receptors, CRF1 and CRF2, are a family of ancient peptide hormones found in all chordates (Figure 1A–C)
The mammalian corticotropin-releasing factor (CRF) receptors and the fly diuretic hormone receptors appear to have evolved from a common ancestral G protein-coupled receptor, seb-2, which is present in worms, including Caenorhabditis elegans (Figure 1C)
Summary
Corticotropin-releasing factor/hormone (CRF or CRH), urocortins, their paralogs, urotensin-I and sauvagine, and their two known G protein-coupled receptors, CRF1 and CRF2 , are a family of ancient peptide hormones found in all chordates (Figure 1A–C). CRF has overlapping physiological functions with the three urocortins, and together, these peptides regulate glucocorticoid and catecholamine release, energy metabolism, reproduction, cardiovascular, and immune functions, to list a few [3]. We will first touch the CRF system differs between males and females in these organs is poorly understood In this upon thewe components of the CRFthe system and literature about what is known about the review, will first touch upon components ofreview the CRF system and review literature about sex-specific actions of the these hormonesactions and their receptors. The activation of CRF1 receptors by CRF inbythe hypothalamus initiates initiates the hypothalamic–pituitary–adrenal axis,resulting resulting in glucocorticoids the release of the hypothalamic–pituitary–adrenal (HPA) axis,(HPA). Hormones of the hypothalamic–pituitary–adrenal and gonadal axes regulate a plethora of functions that include immune, metabolic, and reproduction [21,22]
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