User:Sofianeuroendocrinology/sandbox

Below is my proposed edit for the Corticotropin-Releasing Hormone Receptor 1 page (to be inserted before the section on function).

Structure
The human CRHR1 gene contains 14 exons over 20 kb of DNA, and its full gene product is a peptide composed of 444 amino acids. Excision of exon 6 yields in the mRNA for the primary functional CRF1, which is a peptide composed of 415 amino acids, arranged in seven hydrophobic alpha-helices.

The CRHR1 gene is alternatively spliced into a series of variants. 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. 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. Such structural changes suggest that the alternate CRF1 receptors have different degrees of capacity and efficiency in binding CRF and its agonists. Though the functions of these CRF1 receptors is yet unknown, they are suspected to be biologically significant.

CRF1 is 70% homologous with the second human CRF receptor family, CRF2; the greatest divergence between the two lies at the N-terminus of the protein.

Mechanism of Activation
CRF1 is activated through the binding of CRF or a CRF-agonist. The ligand binding and subsequent receptor conformational change depends on three different sites in the second and third extracellular domains of CRF1.

In the majority of tissues, CRF1 is coupled to a stimulatory G-protein that activates the adenylyl cyclase signaling pathway, and ligand-binding triggers an increase in cAMP levels. However, the signal can be transmitted along multiple signal transduction cascades, according to the structure of the receptor and the region of its expression. Alternate signaling pathways activated by CRF1 include PKC and MAPK. This wide variety of cascades suggests that CRF1 mediates tissue-specific responses to CRF and CRF-agonists.

Tissue Distribution
CRF1 is expressed widely throughout both the central and peripheral nervous systems. In the central nervous system, CRF1 is particularly found in the cortex, cerebellum, amygdala, hippocampus, olfactory bulb, ventral tegmental area, brainstem areas, and pituitary. 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. In the peripheral nervous system, CRF1 is expressed at at low levels in a wide variety of tissues, including the skin, spleen, heart, liver, adipose tissue, placenta, ovary, testis, and adrenal gland.

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. However, the effect of CRF1 appears 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. 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.