Dysregulation of the corticotropin-releasing factor (CRF)-urocortin (UCN) system has been implicated in stress-related psychopathologies such as depression and anxiety. It has been proposed that CRF-CRF receptor type 1 (CRFR1) signalling promotes the stress response and anxiety-like behaviour, whereas UCNs and CRFR2 activation mediate stress recovery and the restoration of homeostasis. Recent findings, however, provide clear evidence that this view is overly simplistic. Instead, a more complex picture has emerged that suggests that there are brain region- and cell type-specific effects of CRFR signalling that are influenced by the individual's prior experience and that shape molecular, cellular and ultimately behavioural responses to stressful challenges.

Region-specific roles of the corticotropin-releasing factor-urocortin system in stress

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 corticotropin-releasing 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.

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

The trafficking of G protein coupled-receptors (GPCRs) is one of the most exciting areas in cell biology because of recent advances demonstrating that GPCR signaling is spatially encoded. GPCRs, acting in a diverse array of physiological systems, can have differential signaling consequences depending on their subcellular localization. At the plasma membrane, GPCR organization could fine-tune the initial stages of receptor signaling by determining the magnitude of signaling and the type of effectors to which receptors can couple. This organization is mediated by the lipid composition of the plasma membrane, receptor-receptor interactions, and receptor interactions with intracellular scaffolding proteins. GPCR organization is subsequently changed by ligand binding and the regulated endocytosis of these receptors. Activated GPCRs can modulate the dynamics of their own endocytosis through changing clathrin-coated pit dynamics, and through the scaffolding adaptor protein β-arrestin. This endocytic regulation has signaling consequences, predominantly through modulation of the MAPK cascade. This review explores what is known about receptor sorting at the plasma membrane, protein partners that control receptor endocytosis, and the ways in which receptor sorting at the plasma membrane regulates downstream trafficking and signaling.

Regulation of G protein-coupled receptor signaling by plasma membrane organization and endocytosis

The CRF System as a Therapeutic Target for Neuropsychiatric Disorders

https://hal.archives-ouvertes.fr/hal-01604784/document

β-arrestin signalling and bias in hormone-responsive GPCRs.

PSD-95 regulates CRFR1 localization, trafficking and β-arrestin2 recruitment

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PSD-95 regulates CRFR1 localization, trafficking and β-arrestin2 recruitment