Homeostatic regulation of neuroendocrine stress by the CRF/Urocortin peptide family and their receptors

[email protected] All living organisms struggle towards maintaining a dynamic equilibrium called homeostasis. Physiological or psychological stimuli that disrupt the organism’s homeostatic equilibrium are known as stressors. The stressors trigger a series of coordinated physiological and behavioral responses, known as the stress response, aimed to enhance the probability of survival by protecting homeostatic equilibrium. Maintenance of homeostasis in the presence of real or perceived challenges requires numerous adaptive responses involving changes in the central nervous, endocrine and immune systems. When a situation is perceived as stressful the brain activates many neuronal circuits to adapt to the demand. Corticotropin releasing factor (CRF), originally isolated from hypothalamus, plays an important and well established role in the regulation of the hypothalamuspituitary-adrenal (HPA) axis under basal and stress conditions (Fig. 1A). In addition to its hypophysiotropic action, CRF is proposed to integrate the endocrine, autonomic and behavioral responses to stressors (Fig. 1A). CRF and its receptors are implicated in the control of arousal, anxiety, cognitive functions and appetite. Dysregulation of the stress response can have severe psychological and physiological consequences. Chronic hyperactivation of the CRF system has been linked to stress-related emotional disorders such as anxiety, anorexia nervosa and melancholic depression. In addition to CRF, the mammalian CRF-peptide family contains urocortin 1, and the recently identified peptides, urocortin 2 and urocortin 3 (Fig. 1B). The effects of CRF-related peptides are mediated through activation of two known receptors, CRF receptor type 1 (CRFR1), and CRFR2 (Fig 1B). CRFR1 mRNA is widely expressed in mammalian brain and pituitary, with high levels in the anterior pituitary, cerebral cortex, cerebellum, amygdala, hippocampus and olfactory bulb. CRFR2 mRNA is expressed in a discrete pattern in the brain with highest densities in the lateral septal nucleus, bed nucleus of the stria terminalis, ventromedial hypothalamic nucleus, olfactory bulb, mesencephalic raphe nuclei and medial amygdala. Receptor binding and intracellular cAMP accumulation studies in cells stably transfected with CRF receptors have demonstrated that CRFR1 and CRFR2 differ pharmacologically. CRF has relatively lower affinity for CRFR2 compared to its affinity for CRFR1, Ucn 1 has equal affinities for both receptors, and Ucn 2 and Ucn 3 appear to be selective for CRFR2 (Fig. 1B).