Definition
Corticotropin-releasing factor (CRF) represents an early chemical signal of the stress response and activates the hypothalamus–pituitary–adrenal axis in response to a stressful stimulus.
Discovery
The existence of CRF was first proposed in 1955 by Guillemin and Rosenberg and Saffran and Schally. Initially isolated from ovine hypothalamus and characterized as a 41 amino acidpeptide in 1981, CRF was subsequently characterizedfrom rat hypothalami, and the identical structure was deduced for human CRF on the basis of the cDNA sequence of the human CRF precursor gene 1,2. Eckart K et al., in 2001 developed strategies permitting synthesis of CRF analogs for CRFBP or CRFR without cross-reaction. They found that one residue of the ARAE motif served as a switch enhancing or preventing ligand binding to CRFBP. This knowledge was applied to the development of peptidic CRF agonists and antagonists 3.
Structural Characteristics
CRF is a 41- amino acid peptide, was originally isolated from the hypothalamus. The stretch of amino acid residues 22–25, Ala-Arg-Ala-Glu, of human/rat CRF, representing the ARAE motif, was found to be responsible for the high affinity of hyrCRF to CRFBP, in contrast to the low affinity of ovine CRF containing the sequence Thr-Lys-Ala-Asp instead. Interestingly, each residue of the ARAE sequence contributed to the high affinity of hyrCRF, as was demonstrated by single residue exchanges. Although sauvagine (Svg), another peptide of the CRF peptide family, binds to CRFBP with only low affinity, the Svg analog containing the ARAE sequence, instead of Glu21-Lys22-Gln23-Glu24, binds with high affinity. However, it has not yet been investigated whether all residues of the ARAE motif are important 4,5. Specific modifications and substitutions of CRF that led to the discovery of antagonists with extended duration of action as compared to that of astressin {cyclo(30−33)[dPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(12-41)}. These additional modifications included elongation of the peptide chain by three residues at the N-terminus, its acetylation, and the [CαMeLeu27] substitution to yield cyclo(30−33)[dPhe12, Nle21,CαMeLeu27,Glu30,Lys33,Nle38]Ac-hCRF(9-41), which was found to be longer acting than astressin which further increases the efficiency (potency, duration of action, and bioavailability) of this family of antagonists 6.
Mode of Action
CRF exhibits its biologic actions through G rotein-dependent receptors. To date, mainly two subtypes of CRF receptors (CRFRs), CRFR1 and CRFR2, have been identified. The central actions of CRF-like peptides are also modulated by the water-soluble CRF binding protein (CRFBP). Consistent with the results of experiments on CRFBP deficient mice, the physiological role of endogenous CRFBP in the central nervous system limit the availability of free ligand for CRFR-mediated actions in brain regions where CRFBP, CRFR, and CRF are colocalized. In addition, central injection of CRF antagonists such as a-helical CRF9–41 (a-hel-CRF9–41), which are bound by CRFBP with high affinity, release endogenous CRF by displacement from CRFBP. The CRF antagonist anti-Svg-30 (aSvg-30) is selective for CRFR2 and useful in in vivo experiments because of its high solubility in cerebrospinal fluid (CSF), the antagonists a-hel-CRF9–41 and Ast are not selective, and bind with different affinities to CRFBP, CRFR1, and CRFR2 7,8.
Functions
Homeostasis, CRF plays a major role in the maintenance or restoration of homeostasis by stimulating the activity of the hypothalamic-pituitary-adrenal (HPA) axis.
Biological function, it also acts within the brain to control immune, reproductive and cardiovascular functions as well as catecholamine release, drug withdrawal, behavior, mood, and anxiety thereby implicating CRF not only as central mediator of stress responses, but also in a variety of stress srelated or -unrelated peripheral functions 9.
On central nervous system, CRF mediates the hypothalamic-pituitary-adrenocortical stress axis. CRF was later found to be widely distributed also outside the hypothalamus throughout the central nervous system 8.
Neurotransmitter, CRF functions as a neurotransmitter or neuromodulator eliciting a wide spectrum of autonomic, electrophysiological, and behavioral effects.
Peripheral sites, in addition to pituitary and central nervous system effects, some effects of CRF in vitro and in vivo have been found at various peripheral sites, where specific binding sites for CRF or messenger RNA (mRNA) for CRF receptors have been localized as well 1.
References
1. Guillemin R, Rosenberg B (1955). Humoral hypothalamic control of anterior pituitary: a study with combined tissue cultures. Endocrinology, 57:599-607.
2. Shibahara S, Morimoto Y, Furutani Y, Notake M, Takahashi H, Shimizu S, Horikawa S, Numa S (1983). Isolation and sequence analysis of the human corticotropin-releasing factor precursor gene. Embo. J., 2(5):775-779.
3. Eckart K, Jahn O, Radulovic J, Tezval H, van Werven L, Spiess J (2001). A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: Implications for the design of agonists and antagonists. PNAS., 98(20):11142-11147.
4. Sutton SW, Behan DP, Lahrichi SL, Kaiser R, Corrigan A, Lowry P, Potter E, Perrin MH, Rivier J, Vale WW (1995). Ligand requirements of the human corticotropin-releasing factor-binding protein. Endocrinology, 136(3):1097-1102.
5. Jahn O, Eckart K, Sydow S, Hofmann BA, Spiess J (2001). Pharmacological characterization of recombinant rat corticotropin releasing factor binding protein using different sauvagine analogs. Peptides, 22(1):47–56.
6. Rivier JE, Kirby DA, Lahrichi SL, Corrigan A, Vale WW, Rivier CL (1999). Constrained corticotropin releasing factor antagonists (astressin analogues) with long duration of action in the rat. J. Med. Chem., 42(16):3175–3182.
7. Spiess J, Dautzenberg FM, Sydow S, Hauger RL, Rühmann A, Blank T, Radulovic J (1998). Molecular Properties of the CRF Receptor. Trends Endocrinol Metab., 9(4):140–145.
8. Brauns O, Liepold T, Radulovic J, Spiess J (2001). Pharmacological and chemical properties of astressin, antisauvagine-30 and alpha-helCRF: significance for behavioral experiments. Neuropharmacology, 41:507–516.
9. Gulyas J, Rivier C, Perrin M, Koerber SC, Sutton S, Corrigan A, Lahrichi SL, Craig AG, Vale W, Rivier J (1995). Potent, structurally constrained agonists and competitive antagonists of corticotropin-releasing factor. PNAS,. 92(23):10575-10579.
