Alcoholism, corticotropin-releasing factor, and molecular genetic allostasis.
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ABSTRACT:
SUBMITTER: Koob GF
PROVIDER: S-EPMC2386996 | biostudies-literature | 2008 Jan
REPOSITORIES: biostudies-literature
Publications
Alcoholism, corticotropin-releasing factor, and molecular genetic allostasis.
Biological psychiatry 20080101 2
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Project description: Not available
| S-EPMC2884668 | biostudies-literature
Project description:Drug addiction is a complex disorder that is characterized by compulsivity to seek and take the drug, loss of control in limiting intake of the drug, and emergence of a withdrawal syndrome in the absence of the drug. The transition from casual drug use to dependence is mediated by changes in reward and brain stress functions and has been linked to a shift from positive reinforcement to negative reinforcement. The recruitment of brain stress systems mediates the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms, defined as the "dark side" of addiction. In this chapter we focus on behavioral and cellular neuropharmacological studies that have implicated brain stress systems (i.e., corticotropin-releasing factor [CRF]) in the transition to addiction and the predominant brain regions involved. We also discuss the implication of CRF recruitment in compulsive eating disorders.
| S-EPMC6155477 | biostudies-literature
Project description:The bimolecular interaction between corticotropin-releasing factor (CRF), a neuropeptide, and its type 1 receptor (CRFR1), a class B G-protein-coupled receptor (GPCR), is crucial for activation of the hypothalamic-pituitary-adrenal axis in response to stress, and has been a target of intense drug design for the treatment of anxiety, depression, and related disorders. As a class B GPCR, CRFR1 contains an N-terminal extracellular domain (ECD) that provides the primary ligand binding determinants. Here we present three crystal structures of the human CRFR1 ECD, one in a ligand-free form and two in distinct CRF-bound states. The CRFR1 ECD adopts the alpha-beta-betaalpha fold observed for other class B GPCR ECDs, but the N-terminal alpha-helix is significantly shorter and does not contact CRF. CRF adopts a continuous alpha-helix that docks in a hydrophobic surface of the ECD that is distinct from the peptide-binding site of other class B GPCRs, thereby providing a basis for the specificity of ligand recognition between CRFR1 and other class B GPCRs. The binding of CRF is accompanied by clamp-like conformational changes of two loops of the receptor that anchor the CRF C terminus, including the C-terminal amide group. These structural studies provide a molecular framework for understanding peptide binding and specificity by the CRF receptors as well as a template for designing potent and selective CRFR1 antagonists for therapeutic applications.
| S-EPMC2583312 | biostudies-literature
Project description:Recent technical advances have greatly facilitated G-protein coupled receptors crystallography as evidenced by the number of successful x-ray structures that have been reported recently. These technical advances include novel detergents, specialised crystallography techniques as well as protein engineering solutions such as fusions and conformational thermostabilisation. Using conformational thermostabilisation, it is possible to generate variants of GPCRs that exhibit significantly increased stability in detergent micelles whilst preferentially occupying a single conformation. In this paper we describe for the first time the application of this technique to a member of a class B GPCR, the corticotropin releasing factor receptor 1 (CRF1R). Mutational screening in the presence of the inverse agonist, CP-376395, resulted in the identification of a construct with twelve point mutations that exhibited significantly increased thermal stability in a range of detergents. We further describe the subsequent construct engineering steps that eventually yielded a crystallisation-ready construct which recently led to the solution of the first x-ray structure of a class B receptor. Finally, we have used molecular dynamic simulation to provide structural insight into CRF1R instability as well as the stabilising effects of the mutants, which may be extended to other class B receptors considering the high degree of structural conservation.
| S-EPMC4498186 | biostudies-literature
Project description:Corticotropin releasing factor (CRF) receptor antagonists have been sought since the stress-secreted peptide was isolated in 1981. Although evidence is mixed concerning the efficacy of CRF(1) antagonists as antidepressants, CRF(1) antagonists might be novel pharmacotherapies for anxiety and addiction. Progress in understanding the two-domain model of ligand-receptor interactions for CRF family receptors might yield chemically novel CRF(1) receptor antagonists, including peptide CRF(1) antagonists, antagonists with signal transduction selectivity and nonpeptide CRF(1) antagonists that act via the extracellular (rather than transmembrane) domains. Novel ligands that conform to the prevalent pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic utility of CRF(1) antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome.
| S-EPMC2864802 | biostudies-literature
Project description:The central amygdala (CeA) is a critical regulator of emotional behavior that has been implicated in psychiatric illnesses, including anxiety disorders and addiction. The CeA corticotropin releasing factor receptor 1 (CRF1) system has been implicated in alcohol use disorder (AUD) and mood disorders, and has been shown to regulate anxiety-like behavior and alcohol consumption in rodents. However, the effects of CRF signaling within the CRF receptor 1-containing (CRF1+) population of the CeA remain unclear, and the effects of ethanol and CRF1 manipulations in female rodents have not been assessed. Here, we characterized inhibitory control and CRF1 signaling in male and female CRF1-GFP reporter mice. Male and female CRF1+ CeA neurons exhibited similar baseline GABAergic signaling and excitability and were comparably sensitive to CRF-induced increases in presynaptic GABA release. CRF1 antagonism reduced GABA release onto CRF1-containing neurons comparably in both males and females. Acute ethanol application reduced GABA release onto CRF1+ neurons from males, but female CRF1+ neurons were insensitive to ethanol. Exogenous CRF increased the firing rate of CRF1-containing neurons to a greater extent in male cells versus female cells, and CRF1 antagonism reduced firing in females but not males. Together, these findings indicate a critical sex-specific role for the CRF system in regulating inhibitory control and excitability of CRF1-containing neurons in the central amygdala. Sex differences in sensitivity of CRF/CRF1 signaling provide useful context for the sex differences in psychiatric illness reported in human patients, particularly AUD.
| S-EPMC8207535 | biostudies-literature
Project description:Background and aimsLoss of the endotoxin tolerance of intestinal epithelium contributes to a number of intestinal diseases. The etiology is not clear. Psychological stress is proposed to compromise the intestinal barrier function. The present study aims to elucidate the role of the stress-derived corticotropin releasing factor (CRF) in breaching the established intestinal epithelial endotoxin tolerance.MethodsEpithelial cells of HT-29, T84 and MDCK were exposed to lipopolysaccharide to induce the endotoxin tolerance; the cells were then stimulated with CRF. The epithelial barrier function was determined using as indicators of the endotoxin tolerant status. A water-avoid stress mouse model was employed to test the role of CRF in breaching the established endotoxin tolerance in the intestine.ResultsThe established endotoxin tolerance in the epithelial cell monolayers was broken down by a sequent exposure to CRF and LPS manifesting a marked drop of the transepithelial resistance (TER) and an increase in the permeability to a macromolecular tracer, horseradish peroxidase (HRP). The exposure to CRF also increased the expression of Cldn2 in the epithelial cells, which could be mimicked by over expression of TLR4 in epithelial cells. Over expression of Cldn2 resulted in low TER in epithelial monolayers and high permeability to HRP. After treating mice with the 10-day chronic stress, the intestinal epithelial barrier function was markedly compromised, which could be prevented by blocking either CRF, or TLR4, or Cldn2.ConclusionsPsychological stress-derived CRF can breach the established endotoxin tolerance in the intestinal mucosa.
| S-EPMC3686760 | biostudies-literature
Project description:The structural analysis of class B G protein-coupled receptors (GPCR), cell surface proteins responding to peptide hormones, has until recently been restricted to the extracellular domain (ECD). Corticotropin-releasing factor receptor type 1 (CRF1R) is a class B receptor mediating stress response and also considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of human CRF1R in complex with the small-molecule antagonist CP-376395 in a hexagonal setting with translational non-crystallographic symmetry. Molecular dynamics and metadynamics simulations on this novel structure and the existing TMD structure for CRF1R provides insight as to how the small molecule ligand gains access to the induced-fit allosteric binding site with implications for the observed selectivity against CRF2R. Furthermore, molecular dynamics simulations performed using a full-length receptor model point to key interactions between the ECD and extracellular loop 3 of the TMD providing insight into the full inactive state of multidomain class B GPCRs.
| S-EPMC5684783 | biostudies-literature
Project description:Drug addiction is a chronically relapsing disorder that is characterized by a compulsion to take drugs and loss of control in limiting intake. Medications that are on the market for the treatment of drug addiction target either the direct reinforcing effects of abuse (eg, naltrexone) or the consequent protracted abstinence syndrome (eg, acamprosate). Both conceptual and neurobiological advances in research have suggested that brain stress systems contribute to the withdrawal/negative affect and preoccupation/anticipation stages of the addiction cycle that promote the compulsivity of drug-taking in addiction. Validated animal models of the stress component of addiction and improved understanding of the neurocircuitry and neuropharmacological mechanisms involved in perturbations of this component suggest that corticotropin-releasing factor systems are a viable target for the development of future medications for drug addiction.
| S-EPMC2812895 | biostudies-literature
Project description:In addition to its established role in initiating the endocrine arm of the stress response, corticotropin-releasing factor (CRF) can act in the brain to modulate neural pathways that effect coordinated physiological and behavioral adjustments to stress. Although CRF is expressed in a set of interconnected limbic and autonomic cell groups implicated as primary sites of stress-related peptide action, most of these are lacking or impoverished in CRF receptor (CRFR) expression. Understanding the distribution of functional receptor expression has been hindered by the low resolution of ligand binding approaches and the lack of specific antisera, which have supported immunolocalizations at odds with analyses at the mRNA level. We have generated a transgenic mouse that shows expression of the principal, or type 1, CRFR (CRFR1). This mouse expresses GFP in a cellular distribution that largely mimics that of CRFR1 mRNA and is extensively colocalized with it in individual neurons. GFP-labeled cells display indices of activation (Fos induction) in response to central CRF injection. At the cellular level, GFP labeling marks somatic and proximal dendritic morphology with high resolution and is also localized to axonal projections of at least some labeled cell groups. This includes a presence in synaptic inputs to central autonomic structures such as the central amygdalar nucleus, which is implicated as a stress-related site of CRF action, but lacks cellular CRFR1 expression. These findings validate a new tool for pursuing the role of central CRFR signaling in stress adaptation and suggest means by which the pervasive ligand-receptor mismatch in this system may be reconciled.
| S-EPMC2597626 | biostudies-literature