CRF pathways

Corticotropin-releasing factor (CRF) is well known for its requisite role in initiating the pituitary-adrenal response to stress. Hypothalamic CRF triggers the rapid release of adrenocorticotropin hormone (ACTH) from the anterior pituitary, leading to the synthesis and secretion of glucocorticoids from the adrenal cortex (Vale et al., 1981). Subsequent actions of glucocorticoids affect a wide range of physiologic and metabolic processes with the primal aim of mobilizing energy stores and increasing glucose utilization. In addition, compelling evidence suggests that CRF functions as a neurotransmitter in numerous extra-hypothalamic nuclei (e.g., amygdala, locus coeruleus, bed nucleus of the stria terminalis (BNST), raphe, hippocampus, neocortex) to participate in the recruitment of complementary autonomic and behavioral adaptations to stress (Owens and Nemeroff, 1991; Koob and Heinrichs, 1999). Such adjustments include increased heart rate and blood pressure, enhanced attentive behaviors and suppression of reproductive and feeding behaviors. Thus, CRF has been widely considered a critical integrator of the global response to stress.

Three new members of the mammalian CRF family have been discovered recently. The first of these, urocortin 1, was identified by homology with the fish peptide, urotensin (Vaughan et al., 1995). Subsequently, urocortin 2 and urocortin 3 (in humans referred to as stresscopin-related peptide and stresscopin, respectively) were discovered based on sequence similarity with urocortin 1 (Hsu and

Hsueh, 2001; Lewis et al., 2001; Li et al., 2001; Reyes et al., 2001). Urocortin 1 shares ~50% sequence homology to CRF and exists predominantly in the Edinger-Westphal nucleus and lateral superior olivary nucleus with modest expression in the supraoptic nucleus of the hypothalamus and several brainstem motor nuclei (Vaughan et al., 1995; Bittencourt et al., 1999). Urocortins 2 and 3 are more closely related to each other (~40% homology) than to CRF and urocortin 1, which suggests they may represent a separate branch of the CRF family (Hsu and Hsueh, 2001; Lewis et al., 2001). Both peptides are expressed in distinct brain nuclei known to be involved in stress-related autonomic and behavioral functions (urocortin 2: locus coeruleus, and paraventricular and arcuate hypothalamic nuclei; urocortin 3: medial nucleus of the amygdala and median preoptic nucleus). Studies to determine the functional relevance of these newly identified CRF congeners are currently underway. It is postulated that these peptides mediate some components of the stress response previously attributed to CRF.

CRF-related peptides activate two known G-protein-coupled seven transmembrane receptors, CRF] and CRF2, that are the products of distinct genes (Dautzenberg et al., 2001). The receptors share ~70% homology, but are distinct in their tissue distribution and binding affinities for CRF-related ligands. CRFi receptors are highly expressed in the pituitary, cerebral cortex, hippocampus, medial septal nucleus, cerebellum, and lateral and arcuate hypothalamic nuclei (Chen et al., 2000; van Pett et al., 2000). The CRF2 receptor a, a splice variant of the CRF2 receptor, lies predominantly in subcortical brain regions distinct from the CRFi receptor, including the lateral septal nucleus, amygdaloid nuclei, ventromedial hypothalamus (VMH), bed nucleus of the stria terminalis (BNST), nucleus of the solitary tract (NTS), and dorsal raphe nucleus (van Pett et al., 2000). The CRF2 receptor p is expressed in nonneuronal brain structures (choroid plexus and arterioles) but is highly abundant in the periphery, including heart, skeletal muscle, and gastrointestinal tract (Stenzel et al., 1995). The CRF2 receptor is highly selective for urocortin signaling in that it binds urocortins 1, 2, and 3 with much greater affinity than CRF (Hsu and Hsueh, 2001; Lewis et al., 2001;

Reyes et al., 2001). In contrast, the CRFj receptor binds both CRF and urocortin 1, while showing no appreciable binding to urocortins 2 and 3. Thus, stress responses may be mediated by functionally separate signaling pathways, comprised of putative CRF/CRF, receptor and urocortin/CRF2 receptor pairings. Intriguingly, recent data suggest that these distinct pathways are inversely regulated by stress, which may reflect functional antagonism between the CRF receptor subtypes (Skelton et al., 2000).

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