An integrated map of corticotropin‐releasing hormone signaling pathway

Abstract

Corticotropin-releasing hormone (CRH), also known as corticotropin-releasing factor (CRF), is a 41-amino acid neuropeptide, expressed abundantly by CRH neurons present in the paraventricular nucleus (PVN) of the hypothalamus, and other parts of the brain (Aguilera and Liu 2012; Vale et al. 1981). CRH is also expressed in adrenal gland, immune cells, placenta, testis, spleen, gut, thymus and skin (Dautzenberg and Hauger 2002; Aguilera and Liu 2012). The activity of the hypothalamic CRH neurons varies in resting and stress conditions. Circadian variations have an effect on CRH neuron activity. On stressful stimuli, sensory information is either transmitted directly to the PVN or integrated by the limbic system and transmitted to the CRH neurons via complex monoaminergic and peptidergic neural pathways. This is dependent on the nature, intensity and duration of the stressor. Systemic and metabolic stressors including blood loss, pain, immune challenge and hypoglycemia, which require immediate response, utilize monosynaptic pathways, whereas, psychogenic stressors utilize complex multisynaptic pathways. These neural pathways trigger signaling in CRH neurons, increasing CRH gene transcription and rapid CRH secretion (Aguilera and Liu 2012). The actions of CRH are transduced through CRH receptors, which belong to the class II/secretin-like family of the G-protein coupled receptor (GPCR) superfamily (Martin et al. 2005). There are three types of CRH receptors – type 1 (CRHR1), type 2 (CRHR2) and type 3 (CRHR3). Among these, CRHR3 has not been identified in mammals. CRHR1 and CRHR2 are encoded by different genes. CRHR1 mRNA has several splice variants encoding different isoforms – R1α, R1β, R1c, R1d, R1e, R1f, R1g and R1h, predominant of which is CRHR1α (Chen et al. 1993; Ross et al. 1994; Grammatopoulos et al. 1999; Pisarchik and Slominski 2001, 2004). CRHR1 is expressed predominantly in the CNS, pituitary, heart (Chen et al. 1993) and also in adrenal gland, ovary, and placenta (Grammatopoulos et al. 1999; Seres et al. 2004; Asakura et al. 1997). The gene encoding the human CRHR2 has three mRNA splice variants which encodes 3 isoforms - R2α, R2β and R2γ and is expressed predominantly in brain and heart (Kostich et al. 1998; Yang et al. 2010). CRH is a high-affinity ligand of CRHR1. It also binds to CRHR2, but with lower affinity (Hsu and Hsueh 2001; Grammatopoulos et al. 1999; Wille et al. 1999). CRH receptors do not have any intrinsic kinase activity and the signal is transduced via the heterotrimeric G-proteins (Freissmuth et al. 1989). Biological activity of CRH is regulated by CRH binding protein (CRHBP), which by binding to the former with high affinity, makes it unavailable for binding to CRH receptors (Potter et al. 1991; Behan et al. 1995; Seasholtz et al. 2002). CRHBP is expressed in high levels in the brain, heart, lungs, and placenta (Potter et al. 1991; Behan et al. 1995; Binder and Nemeroff 2010). CRH exerts its functions through activation of several signaling pathways including adenylate cyclase/protein kinase A (PKA), phospholipase C (PLC)/protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) pathways. CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). CRH is involved in the etiologies of several stress-related physiological responses and behavioral responses, such as altered blood pressure, increased arousal, enhanced learning, thermogenesis, anxiogenesis, anhendonia, reduced sleep, psychomotor alterations, decreased appetite and libido (Binder and Nemeroff 2010). CRH, upon binding to hippocampal CRHR1, mediates stress-induced enhancement of fear conditioning and learning. In contrast, CRH by binding to the lateral septal CRHR2 mediates stress-induced anxiety and impairs fear conditioning and learning (Radulovic et al. 1999). Pro-inflammatory and anti-inflammatory responses are exerted through peripheral and central CRH, respectively (Karalis et al. 1991; Friedman and Irwin 2001). Binding of peripheral and central CRH to their receptors were implicated in hemodynamic actions (Yang et al. 2010). Endometrial CRH was found to be involved in stromal cell decidualization during estrus cycle (Zoumakis et al. 2000) and also in implantation of blastocyst (Athanassakis et al. 1999). Placental CRH is involved in the maintenance of pregnancy and onset of labor (McLean et al. 1995). Excess secretion of CRH during severe depression and its association with increased levels of cortisol have been observed (Widerlov et al. 1988). CRH was also reported to be involved in anxiety disorders (Roy-Byrne et al. 1986), and anorexia nervosa (Connan et al. 2007). Decrease in cortical CRH content was observed in Alzheimer’s disease (Heilig et al. 1995) and Parkinson’s disease (Suemaru et al. 1995). Diverse aspects of CRH signaling have been well-studied. Owing to its high biological significance, a detailed documentation of all molecular reactions in a centralized resource and depiction of these reactions into a pathway map is desired in the public domain. Therefore, we have curated each pathway reaction reported downstream to CRH-CRHR interaction and submitted a detailed CRH signaling pathway data to the NetPath (http://www.netpath.org) (Kandasamy et al. 2010). Several such ligand-receptor signaling pathways including Leptin (Nanjappa et al. 2011), TWEAK (Bhattacharjee et al. 2012) and Prolactin (Radhakrishnan et al. 2012), had been developed by our group and submitted to NetPath. Here, we describe the generation of an integrated pathway map of CRH signaling by manual curation.