CRF (OVINE)

The first evidence of a hypothalamic corticotropinreleasing substance was reported in 1955.The presence of a corticotropin-releasing hormone (CRH) was first reported in the ovine hypothalamus in 1981. Subsequently, CRH was found in the human, mouse, rat, pig, amphibian (Xenopus), teleost fish, cartilaginous fish, and lamprey. Novel members of the CRH family, CRH26,  and teleocortin (Tcn), have recently been reported in vertebrates (except teleosts and placental mammals) and the medaka, respectively.

Human/mouse/rat CRH: Mr 4758; pI 5.1. CRH peptides are freely soluble in water. The oxidation of methionine at position 21 remarkably decreases the activity of CRH.

Three types of CRH receptors have been identified.  They belong to the family of seven-transmembrane-domain GPCRs and activate AC. Type-1 (CRHR1) and type-2 (CRHR2) receptors were identified in mammals, chicken, Xenopus, and teleosts. The type-3 receptor (CRHR3) was found in catfish. In mammals, the CRHR1 gene consists of 13 exons and 12 introns. The CRHR2 gene in humans consists of 12 exons and 11 introns, and three splice variants (CRHR2α, 2β, and 2γ) have been found; 2–12 exons are common to the three splice variants, and the first exon is specific for each variant. CRH binds to CRHR1 with high affinity. CRHR1 is mainly distributed in the anterior pituitary, and is involved in ACTH release. CRH also has high affinity to CRHR3. However, CRHR2 exhibits low affinity to CRH but high affinity to urotensin-I,sauvagine, and urocortins. CRHR2 is distributed in several restricted regions of the brain, but also in peripheral organs such as the heart, lung, muscle, and kidney. The CRH binding protein (CRH-BP, 37 kDa) has been highly conserved across evolution from crustaceans to humans. CRH-BP binds to CRH with high affinity and regulates CRH effects. In both mammals and nonmammalian vertebrates, pituitary and brain CRH-BP expression in the brain and pituitary are predominantly increased by stress. In the chicken, CRH2 is more potent in activating CRHR2 than CRHR1. In the medaka, Tcn and CRH have similar receptor interaction properties.

CRH activates AC via Gs protein-coupled with CRHRs. AC stimulates cAMP production, and cAMP, in turn, activates PKA, which phosphorylates downstream of cytosolic and nuclear targets such as CREB, resulting in induced gene transcription. Moreover, it is known that in addition to signaling pathways activated by cAMP, CRHR1 and CRHR2 trigger multiple signaling pathways such as the activation of p42/44 MAPK (ERK1/2).

CRH stimulates the synthesis and processing of proopiomelanocortin (POMC) to generate ACTH in the anterior pituitary. CRH also stimulates ACTH release. ACTH is secreted into the systemic circulation, reaches the adrenal cortex, and stimulates the synthesis and release of glucocorticoids. CRH also acts as a neuromodulator in the brain. CRH in the brain regulates the endocrine system, autonomic nervous system, and immune system in response to stress. In addition to the stress response, CRH is involved in multiple physiological functions such as suppression of food intake, regulation of body temperature, growth, metabolism, metamorphosis, reproduction, and diuresis. In mammals, CRH inhibits the female reproductive axis by suppressing gonadotropinreleasing hormone (GnRH) secretion. CRH2 stimulates TSHβ expression and shows a lower potency in inducing ACTH secretion in vitro in the chicken.

The synthesis and release of CRH are regulated by internal or external stress that is conveyed to the brain and is integrated at the hypothalamus, where CRH neurons exist. The synthesis and release of CRH are also regulated by diurnal rhythm and the negative feedback effect of cortisol. In nocturnal rats, CRH mRNA levels are higher at midday than at midnight. CRH is released from the axon terminal depending on Ca2+.

CRH is a key activator of the hypothalamo-pituitaryadrenal (HPA) axis in response to internal or external stresses by stimulating adrenocorticotropic hormone (ACTH) secretion from the pituitary.

CRF is a hypothalamic peptide that releases ACTH and endorphin from the anterior pituitary. It is also a neurotransmitter in the central nervous system, and is involved in autonomic and endocrine responses to stress.

Clinical implications
Increased CRH production has been suggested to be associated with Alzheimer’s disease and depression. CRH deficiency has been observed to induce hypoglycemia and hepatitis. CRH has been used in the diagnosis of ACTH-dependent Cushing’s syndrome and Addison’s disease.
Use for diagnosis and treatment
CRHR1 antagonists Pexacerfont and Antalarmin are under clinical trial for the treatment of generalized anxiety disorder as well as depression and other mental disorders, respectively

CRH peptides of all species examined consist of 41 aa residues with an amidated C-terminus. The C-terminal region is important for physiological activity. The human, mouse, and rat CRH have identical aa sequences. CRH sequence homologies between human/mouse/rat and others are high (76%–95%). CRH2 peptides consist of 40–43 aa residues with an amidated C-terminus.