The Corticotropin-Releasing Factor Family: Physiology of the Stress Response

Jan M. Deussing, Alon Chen
2018 Physiological Reviews  
The physiological stress response is responsible for the maintenance of homeostasis in the presence of real or perceived challenges. In this function, the brain activates adaptive responses that involve numerous neural circuits and effector molecules to adapt to the current and future demands. A maladaptive stress response has been linked to the etiology of a variety of disorders, such as anxiety and mood disorders, eating disorders, and the metabolic syndrome. The neuropeptide
more » ... easing factor (CRF) and its relatives, the urocortins 1-3, in concert with their receptors (CRFR1, CRFR2), have emerged as central components of the physiological stress response. This central peptidergic system impinges on a broad spectrum of physiological processes that are the basis for successful adaptation and concomitantly integrate autonomic, neuroendocrine, and behavioral stress responses. This review focuses on the physiology of CRF-related peptides and their cognate receptors with the aim of providing a comprehensive up-to-date overview of the field. We describe the major molecular features covering aspects of gene expression and regulation, structural properties, and molecular interactions, as well as mechanisms of signal transduction and their surveillance. In addition, we discuss the large body of published experimental studies focusing on state-of-the-art genetic approaches with high temporal and spatial precision, which collectively aimed to dissect the contribution of CRF-related ligands and receptors to different levels of the stress response. We discuss the controversies in the field and unravel knowledge gaps that might pave the way for future research directions and open up novel opportunities for therapeutic intervention. Pituitary Hypothalamus Adrenal medulla ACTH CRF Adrenal cortex Adrenaline (+ Noradrenaline) Noradrenaline SAM system SN system Cortisol Autonomic nervous system HPA axis Stressor FIGURE 1. Effector systems of the stress response. A stressor elicits rapid activation of the autonomic nervous system with its sympathoneuronal (SN) and sympatho-adrenomedullary (SAM) limbs releasing their main effectors, noradrenaline and adrenaline, respectively. Activation of the hypothalamic-pituitary-adrenocortical (HPA) axis results in synthesis and release of its main effector, cortisol or corticosterone, in rodents. ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor. DEUSSING AND CHEN 2226 Physiol Rev • VOL 98 • OCTOBER 2018 • www.prv.org DEUSSING AND CHEN STRESS AND THE CRF FAMILY 2229 Physiol Rev • VOL 98 • OCTOBER 2018 • www.prv.org B FIGURE 2 . The family of corticotropin-releasing factor (CRF)-related neuropeptides. A: alignment of amino acid sequences of mature CRF-related peptides from vertebrates and of diuretic hormone (DH) from insects. The NH 2 -terminal activating domain is highlighted in light green. The COOH-terminal domain binding to CRFRs' extracellular domain is highlighted in blue. The central linker domain is essential for CRF-binding protein (BP) binding. The CRF-specific Ala-Arg-Ala-Glu motif, which conveys CRF-BP binding, is depicted in brown. The N-capping motif is highlighted in dark green. Amino acid residues conferring CRF receptor type 2 (CRFR2)-specificity are indicated in pink. A three-dimensional structure of CRF is depicted above the alignment. B: phylogenetic tree of the four CRF paralogs in vertebrates. The phylogenetic tree was generated using Phylogeny.fr (140).
doi:10.1152/physrev.00042.2017 pmid:30109816 fatcat:7uvifc2l7baahbt2lb4udn2cvy