Corticotrophin-releasing factor receptor

Several neurotransmitter and receptor changes are observed in Alzheimer s disease (Nordberg 1992). Losses occur in nicotinic receptors, but muscarinic receptors are relatively preserved. Reductions are also seen in serotonin 5-HTl and 5-HT2 receptors. Glutamate NMDA receptors decrease, while kainate receptors increase. j8-adrenergic and dopamine receptors are preserved. Decreases occur in receptors for somatostatin and neuropeptide Y, but corticotrophin-releasing factor receptors increase. Across all receptor subtypes for which there is a loss, the number of receptors decrease but the affinity constant remains unchanged. 

Chalmers DT, Lovenberg TW, Grigoriadis DE, Behan DP, De Souza EB (1997) Corticotrophin-releasing factor receptors from molecular biology to drug design. Trends Pharmacol Sci 17 166-172... 

Flores M, Carvallo P, Aguilera G (1990) Physicochemical characterization of corticotrophin releasing factor receptor in rat pituitary and brain. Life Sci 47(22) 2035—40... 

Hersey. S.J. et al. (1995) Gastric acid secretion. Physiol. Rev.. 75.155-190. antalarmin is a synthetic non-peptide CORTICOTROPHIN-RELEASING factor RECEPTOR ANTAGONIST which is more active at the CRF subtype. It is used as a pharmacological tool, antazoline (ban.inn) (antazoline phosphate [usan] antazollne sulphate imidazolamine phenazoline ... 

CORTICOTROPHIN-RELEASING FACTOR RECEPTOR ANTAGONISTS inhibit the actions of agents related to corticotrophin-releasing factor (CRF). Two subtypes of receptor, CRF, and CRFj. have recently been identiffed and cloned, and there is interest in these as therapeutic targets. See CORTICOTROPHIN-RELEASING FACTOR RECEPTOR AGONISTS. 

Corticotrophin-releasing hormone (CRH corticotrophin-releasing factor. CRF) controls release of corticotrophin (adrenocorticotrophic hormone. ACTH). which in turn controls the release of corticosteroids from the adrenal glands. See corticotrophin-releasing factor RECEPTOR agonists CORTICOTROPHIN-RELEASING FACTOR RECEPTOR ANTAGONISTS. 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

Recent in vitro hybridization studies in the rat have demonstrated that t)rpical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the s)mthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid s)mthesis inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRT) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development. 

Lightman SL, Young WS 3rd (1988) Corticotrophin-releasing factor, vasopressin and proopiomelanocortin mRNA responses to stress and opiates in the rat. J Physiol 403 511-523 Lolait SJ, O Carroll AM, Mahan LC, Felder CC, Button D, Yoimg III WS, et al (1995) Extra-pituitary expression of the rat Vlb vasopressin receptor gene. Proc Natl Acad Sci USA 92 6783-6787... 

Corticotrophin releasing factor ligands - alpha helical CRF has been shown to block the anxiogenic effects of alcohol withdrawal in rats. It is possible that CRF interacts with neuropeptide Y receptors NPY 1 receptor agonists to have anticonflict effects in animal studies. 

The effect of stress on the endocrine and immune systems depends upon its duration and severity. Following acute stress, the rise in ACTH in response to the release of corticotrophin releasing factor (CRF) from the hypothalamus results in a rise in the synthesis and release of cortisol from the adrenals. The increase in the plasma cortisol concentration results in a temporary suppression of many aspects of cellular immunity. Due to the operation of an inhibitory feedback mechanism, stimulation of the central glucocorticoid receptors in the hypothalamus and pituitary causes a decrease in the further release of CRF, thereby decreasing the further... 

Figure 18.3. Endocrine-immune inter-relationship in depression. In depression, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated with a down-regulation of its negative feedback controls. Corticotrophin releasing factor (CRF) is hypersecreted from the hypothalamus and induces the release of adrenocortico-trophic hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

For example, the corticotrophin releasing factor (CRF) receptor patent was held by Neurocrine, and development of candidate molecules by others was thereby effectively inhibited. 

TNF-a and increasing IL-8 (Webster et al., 2002). Consistent with this, selective receptor antagonists such as butox-amine can antagonize the corticotrophin-releasing factor-induced reduction in natural killer (NK) cell activity (Irwdn et al., 1990). Sympathetic nerve stimulation also enhances T 2 cytokine production while inhibiting cytokine production. Thus, pj receptor agonists can suppress interferon-y (IFN-y) production by cells, an effect, which can be blocked by propranolol. Interestingly, prion presence in the brain has been linked to an interaction between splenic monocytic cells and the sympathetic nervous system (Steinman, 2004). 

I Given the role of the lypothalaniic-pituitaiy-adrenal (HP A) axis in depression, corticotrophin-releasing factor (CRF) receptors (CRFi, CRF2) antagonists are currently under clinical evaluation as antidepressants. 

Calcitonin Receptor-Like Calcitonin Receptor Corticotrophin Releasing Fact s Cortlcotrophln Releasing Fa> Corticotrophin Releasing Factor Gastric Inhibitory Peptide Receptor Glucagon>llke Receptor... 

CRF Corticotrophin-releasing factor NKi Neurokinin receptor, type 1... 

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