RESUMO
The biology of corticotropin-releasing factor (CRF) finds increasing interest in the scientific community because of the neuromodulatory actions of CRF on brain functions such as learning, anxiety, feeding, and locomotion. Additional actions on immunumodulation and apoptosis have recently been discovered. All actions of CRF are mediated by G protein-coupled receptors, which trigger different, sometimes opposite actions in different regions of the central nervous system. The CRF system exhibits considerable plasticity by the involvement of numerous different ligands, splice variants, and transductional couplings. The generation of multiple splice variants is facilitated by the intron exon structure of the CRF receptor genes.
Assuntos
Receptores de Hormônio Liberador da Corticotropina/metabolismo , Sequência de Aminoácidos , Animais , Apoptose/fisiologia , Comportamento/fisiologia , Sítios de Ligação , Proteínas de Transporte/metabolismo , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Proteínas de Ligação ao GTP/metabolismo , Humanos , Ligantes , Dados de Sequência Molecular , Neurônios/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Alinhamento de Sequência , Transdução de SinaisRESUMO
Corticotropin releasing factor (CRF) represents an early chemical signal in the stress response and modulates various brain functions through G protein-coupled receptors. Two CRF receptor subtypes, CRF(1) and CRF(2), have been identified. Since the physicochemical properties of CRF receptor antagonists might influence their biological potency, the peptidic antagonists astressin, alpha-helical CRF(9-41) (alpha-helCRF) and antisauvagine-30 (aSvg-30) have been analyzed. The rank order of solubility of these compounds in artificial cerebrospinal fluid (aCSF, pH 7.4) was aSvg-30>alpha-helCRF>>astressin, whereas the rank order of relative lipophilicity as determined with RP-HPLC was alpha-helCRF>astressin>aSvg-30. The calculated isoelectric points were 4.1 (alpha-helCRF), 7.4 (astressin) and 10.0 (aSvg-30). According to Schild analysis of the CRF receptor-dependent cAMP production of transfected HEK cells, aSvg-30 exhibited a competitive antagonism and displayed a 340 fold selectivity for mCRF(2 beta) receptor. For astressin, however, the pharmacodynamic profile could not be explained by a simple competitive mechanism as indicated by Schild slopes >1 for rCRF(1) or mCRF(2 beta) receptor. Behavioral experiments demonstrated that after i.c.v. injection, alpha-helCRF reduced oCRF-induced anxiety-like behavior in the elevated plus-maze, whereas astressin, despite its higher in vitro potency, did not. These findings could be explained by different physicochemical properties of the antagonists employed.
