Studies on the metabolism of corticotropin-releasing factor

Corticotropin-releasing factor (CRF) is the primary central nervous system (CNS) chemical messenger that regulates pituitary-adrenal axis activity. There is considerable evidence that CRF is also synthesized within neurons, at several extrahypothalamic sites, and in the periphery. In the CNS, CRF functions as a neurotransmitter or neuromodulator. In the periphery, the function of CRF is largely unknown, but it may act as an autocrine or paracrine hormone modulating local endocrine responses and immune function. Little is known concerning the termination of action of this important peptide and the actions of the putative ectopeptidases involved have not previously been characterized.; The purpose of this study was to evaluate the hypothesis that specific ectopeptidases degrade CRF in the pituitary and CNS. Moreover, due to structural homologies, the role of angiotensin converting enzyme (ACE, E.C.3.4.15.1) in the metabolism of CRF was given special consideration. The activity of three purified ectopeptidases: ACE; endopeptidase 24.11 (NEP, E.C.3.4.24.11); and aminopeptidase N (AP-N, E.C.3.4.11.2) on rat/human CRF{dollar}sb{lcub}1-41{rcub}{dollar} was assessed using high performance liquid chromatography and protein sequencing. Next, the ability of specific enzyme inhibitors to modulate the action of CRF in an anterior pituitary culture system was determined. Finally, the action of specific enzyme inhibitors in protecting r/h CRF from degradation in rat cortex, hypothalamus, and pituitary membrane preparations was evaluated.; ACE, NEP, and AP-N were shown to be capable of hydrolyzing r/h CRF and the metabolic profile of each is described. Analysis of the kinetic parameters for ACE action on CRF casts doubt on the physiological significance of this enzyme in CRF metabolism. Inhibition of NEP and aminopeptidase activity were observed to slow CRF degradation by rat pituitary and hypothalamic membranes and to increase CRF-induced ACTH release in the anterior pituitary. CRF metabolism in the cerebral cortex does not appear to involve either ACE, NEP, or a bestatin sensitive aminopeptidase.; These findings support the hypothesis that CRF function is modulated by the ectopeptidases, specifically NEP and the bestatin sensitive aminopeptidases.