(what, action, synthesis, packaging, relevance)
- Small proteins or polypeptides that act as neurotransmitters
- Usually act via GPCRs
- Synthesis requires transcription & translation
- Synthesised as large precursor prepropeptides
- Packaged in large dense-core vesicles
- May diffuse far from release site
- Provide another layer of modulation
- May be good targets for therapy but more work needed
What is CRF and why may or may not it be a good target for drug therapeutics?
Corticotropin Releasing Factor - 41 amino-acid peptide synthesised in the hypothalamus and released in brain regions through the portal system, acting on the pituitary to trigger the release of corticotropin.
CRF1: widely expressed in CNS, ligands are CRF and urocortin
CRF2: narrow expression - lateral septum, ligands are UNC2 & UNC3
There has been interest in CRF in the treatment of anxiety and depression. It is key in coordinating the behavioural and metabolic response to stress. Experiments have shown that stress favours the development of depression and anxiety. CRFR1 mutations are also associated with depression and anxiety.
In mice, CRF administration increases behavioural stress. "High-stress mice" have high CRF levels, and CRFR1 overexpressing mice have higher behavioural stress. Thus, CRFR1 antagonists have been sought, as such a drug would suppress behavioural changes associated with stress.
Clinical success of CRF1R antagonists for anxiety and depression, however, have shown mixed results of lacking success. Animal studies were positive, but were modelled poorly, \through choice of species or test (e.g. forced swim test), and hence did not translate to human effect. Very homogenous populations were used, which may have contributed to this result. In future, genetic testing may be needed to find the right population for CRF effect. (Also, no pet ligands for CRFR1 to allow drug concentration determinations)