[7] Excision of exon 6 yields in the mRNA for the primary functional CRF1,[7] which is a peptide composed of 415 amino acids, arranged in seven hydrophobic alpha-helices.

[7][9] 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.

[9] Such structural changes suggest that the alternate CRF1 receptors have different degrees of capacity and efficiency in binding CRF and its agonists.

[7][8][9] The ligand binding and subsequent receptor conformational change depends on three different sites in the second and third extracellular domains of CRF1.

[9] 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.

[12] In mice, offspring born to CRF1 -/- knockout mothers typically die within a few days of birth from lung dysplasia, likely due to low glucocorticoid levels.

[13] 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.

[16] Corticotrophin releasing hormone (CRH) evolved ~500 million years ago in an organism that subsequently gave rise to both chordates and arthropods.