A Corticotropin-Releasing Hormone Antagonist (CRH antagonist) is a specific type of receptor antagonist that blocks the receptor sites for Corticotropin-releasing hormone (also known as Corticotropin-releasing factor (CRF)), which synchronizes the behavioral, endocrine, autonomic, and immune responses to stress by controlling the hypothalamic-pituitary-adrenal axis (HPA Axis).[1] CRH Antagonists thereby block the consequent secretions of ACTH and cortisol due to stress, among other effects.
There are four subtypes of the CRH receptor known at present, defined as CRF-1, CRF-2a, CRF-2b, and CRF-2g. Three of these receptors are expressed only in the brain: CRF-1 in the cortex and cerebrum, CRF-2a in the lateral septum and hypothalamus, and CRF-2g in the amygdala. CRF-2b is expressed in the choroid plexus and cerebral arterioles in the brain, but is expressed mainly peripherally on the heart and skeletal muscle tissue.[2] Extensive research has shown that overactivity in the brain CRF-CRF1 signaling system contributes to the onset of anxiety disorders and depression. It's been hypothesized that patients with clinical conditions that are causally related to HPA hyperactivity, including major depression and post-traumatic stress disorders, may benefit from CRH receptor antagonist treatment. CRH antagonists are believed to work by blocking the consequent secretions of ACTH and cortisol that occur following activation of CRH and lowering the stress-induced rise of CRH in CSF. There is increased clinical interest in CRH receptor antagonists that can cross the blood-brain barrier for the treatment of depression and anxiety, along with other conditions related to HPA hyperactivity, including treatment of irritable bowel syndrome, which is exasperated by stress.[3][4]
CRH is produced by parvocellular neuroendocrine cells within the paraventricular nucleus of the hypothalamus and is released at the median eminence from neurosecretory terminals of these neurons into the primary capillary plexus of the hypothalamo-hypophyseal portal system. The portal system carries the CRH to the anterior lobe of the pituitary, where it stimulates corticotropes to secrete adrenocorticotropic hormone (ACTH) and other biologically-active substances (β-endorphin). ACTH stimulates the synthesis of cortisol, glucocorticoids, mineralocorticoids and DHEA.[7]
In the short term, CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention. Although the distal action of CRH is immunosuppression via the action of cortisol, CRH itself can actually heighten inflammation, a process being investigated in multiple sclerosis research.[8]
The CRHR1 gene is alternatively spliced into a series of variants.[8][11] These variants are generated through deletion of one of the 14 exons, which in some cases causes a frame-shift in the open reading frame, and encode corresponding isoforms of CRF1.[8][10] Though these isoforms have not been identified in native tissues, the mutations of the splice variants of mRNA suggest the existence of alternate CRF receptors, with differences in intracellular loops or deletions in N-terminus or transmembrane domains.[10] Such structural changes suggest that the alternate CRF1 receptors have different degrees of capacity and efficiency in binding CRF and its agonists.[8][10][11] Though the functions of these CRF1 receptors is yet unknown, they are suspected to be biologically significant.[10]
CRF1 is expressed widely throughout both the central and peripheral nervous systems.[10] In the central nervous system, CRF1 is particularly found in the cortex, cerebellum, amygdala, hippocampus, olfactory bulb, ventral tegmental area, brainstem areas, and pituitary.[8][9][12] In the pituitary, CRF1 stimulation triggers the activation of the POMC gene, which in turn causes the release of ACTH and β-endorphins from the anterior pituitary.[8] In the peripheral nervous system, CRF1 is expressed at low levels in a wide variety of tissues, including the skin, spleen, heart, liver, adipose tissue, placenta, ovary, testis, and adrenal gland.[8][9][11]
In CRF1 knockout mice, and mice treated with a CRF1 antagonist, there is a decrease in anxious behavior and a blunted stress response, suggesting that CRF1 mechanisms are anxiogenic.[8][12] However, the effect of CRF1appears to be regionally specific and cell-type specific, likely due to the wide variety of cascades and signaling pathways activated by the binding of CRF or CRF-agonists.[12] In the central nervous system, CRF1 activation mediates fear learning and consolidation in the extended amygdala, stress-related modulation of memory formation in the hippocampus, and brainstem regulation of arousal.[12]
The corticotropin-releasing hormone receptor binds corticotropin-releasing hormone, a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress.[13]
CRF1 receptors in mice mediate ethanol enhancement of GABAergic synaptic transmission.[14]
Variations in the CRHR1 gene is associated with enhanced response to inhaled corticosteroid therapy in asthma.[16]
CRF1 triggers cells to release hormones that are linked to stress and anxiety [original reference missing].Hence CRF1 receptor antagonists are being actively studied as possible treatments for depression and anxiety.[17][18]
Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.[19]
Corticotropin-releasing hormone receptors (CRHRs), also known as corticotropin-releasing factor receptors (CRFRs) are a G protein-coupled receptor family that binds corticotropin-releasing hormone (CRH).[1] There are two receptors in the family, designated as type 1 and 2, each encoded by a separate gene (CRHR1 and CRHR2 respectively).
CRHRs are important mediators in the stress response.[2] Cells in the anterior lobe of the pituitary gland known as corticotropes express the receptors and will secrete adrenocorticotropic hormone (ACTH) when stimulated. This binding of corticotropin releasing-hormone (CRH) activates the hypothalamic-pituitary-adrenal (HPA) axis, one of the two parts of the fight-or-flight response to stress.[3] CRHRs are also present in other brain areas such as the amygdala, locus coeruleus and hippocampus. Within the hippocampus, the CRHR1s are most abundant, residing mainly on the pyramidal cells of CA1 and CA3. Chronic activation of CRHR1s by CRH induced by early life stress has been shown to underlie memory deficits and learning impairments and anxiety in adulthood.[citation needed]
Edited by farshad, 22 May 2018 - 06:17 PM.
