In mid-nineties, urocortin (Ucn), a 40 amino acid peptide, was identified as a new member of family a highly evolutionary conserved corticotropin-releasing factor (CRF) peptide discovered earlier in 1981 (Vale et al. 1981). Vaughan and colleagues used a probe derived from urotensin, a fish member of the CRF family, and discovered immunoreactivity in localized rat midbrain region (Vaughan et al. 1995). Urocortin isoforms are widely expressed in the heart, central nervous system, gut, skeletal muscle, skin, and immune system (Davidson et al. 2009). It has several systemic actions associated with stress; it mimics some of CRF effects in the nervous system as it enhanced anxiety and is a potent suppressor of appetite and feeding behavior (Pan and Kastin 2008). Urocortin has strong actions on the cardiovascular system (Diaz and Smani 2013), it evokes positive inotropic and chronotropic effects (Davis et al. 2007; Calderon-Sanchez et al. 2009), it protects cardiac cells from ischemia and reperfusion injuries (Lawrence et al. 2003; Calderón-Sánchez et al. 2016), while it promotes potent vasodilatation in human and rat coronary arteries (Smani et al. 2011). Moreover, urocortin improves dystrophic skeletal muscle structure and function (Reutenauer-Patte et al. 2012) among other systemic effects.
Urocortin Isoforms and Their Distribution
Urocortin includes three isoforms, Ucn-1, Ucn-2, and Ucn-3, exhibiting various degrees of amino acid sequence homology to mammalian CRF (45% sequence identity). The structure of rat Ucn-1 has high homology with fish urotensin (63% sequence identity) and frog sauvagine (35% identity) (Vaughan et al. 1995). Human Ucn-1 has also similar homology to fish urotensin and CRF at the amino acid level, and it is very close (95%) to the rat sequence (Donaldson et al. 1996). Mouse Ucn-2 is a peptide formed by 38 amino acids that has moderate identity with CRF (34%) and Ucn-1 (34%). Another Ucn-2 closely related peptide was also identified in human, but its structure lacks the typical consensus proteolytic cleavage site associated with C-terminal processing. Meanwhile, murine and human Ucn-3 exhibits less homology to other members of the CRF family (18–32%) (Diaz and Smani 2013). Although these urocortin isoforms share moderate sequence identity with each other and appear to stem from an ancestral peptide precursor, nevertheless each isoform has a unique anatomical distribution under the control of different genes. In humans, Ucn-1 is present in the brain, placenta, gastrointestinal track, synovial tissue, lymphocytes, adipose tissue, endothelial cells, and heart. Ucn-2 is mostly expressed in the heart, in discrete areas of the central nervous system, mouse skin, and skeletal muscle (Chen et al. 2004). Meanwhile, Ucn-3 is present in heart’s atria and ventricle, and is abundantly expressed in pituitary gland and hypothalamus region (Diaz and Smani 2013).
Urocortin Receptors: Corticotropin-Releasing Factor Receptors
Urocortin peptide triggers physiological signaling mechanisms via activation of two corticotropin-releasing factor (CRF) receptors: CRF-R1 and CRF-R2. Ucn-1 binds to both receptors whileUcn-2 and Ucn-3 are exclusive CRF-R2 ligands. CRF receptors are membrane-bound proteins that belong to the family of 7 transmembrane G protein-coupled receptors (GPCRs) (Dautzenberg and Hauger 2002). Both receptors are approximately 70% identical at the amino acid level, but each one exhibits considerable divergence at the N-terminus, consistent with their distinct pharmacological properties. Because of the different structure of the ligand-binding domain, CRF-R2 is divided into the alpha, beta, and gamma subtypes. CRF-R1 is predominantly expressed in the brain, the pituitary gland, the cerebellum, and the brainstem; meanwhile it is less present in peripheral tissues (Pan and Kastin 2008). Unlike CRF-R1, CRF-R2 is expressed in a discrete pattern in the brain and only small quantities have been found mainly in areas responsible for modulation of the stress responses such as the olfactory bulb, the hippocampus, the amygdala, the hypothalamic nuclei, etc. However, CRF-R2 is much abundant in the peripheral organs, including the vascular endothelium and smooth muscle cells, the heart, the skeletal muscle, and the fibroblast (Baigent and Lowry 2000).
CRF-R1 and CRF-R2 signal in a variety of cell lines by coupling to Gs protein leading to the stimulation of adenylyl cyclase, cAMP production, and activation of cAMP pathway events as protein kinase A (PKA) and exchange protein activated by cAMP (Epac) (Calderon-Sanchez et al. 2009; Reutenauer-Patte et al. 2012). Nevertheless, urocortin binding to CRF-R1 and CRF-R2 might signal also via Gq-mediated stimulation of phospholipase C (PLC), formation of inositol phosphates, and activation of protein kinase C (PKC) and MAPK (Latchaman 2002).
Urocortin has a wide range of biological actions. The initial studies have focused on its effects in the nervous system especially on stress-related responses. Previous study showed that a triple urocortin knockout mouse model reveals an essential role for urocortin in stress recovery (Neufeld-Cohen et al. 2010). In vivo and in vitro studies demonstrated that urocortin is related to enhanced anxiety and depression (Henckens et al. 2016). Other studies demonstrated that urocortin increases satiety, reduces gut motility (Latchaman 2002), and enhances insulin sensitivity in high fat diet mice (Gao et al. 2016). Urocortin has also a significant effect in skeletal muscle remodeling; indeed the injection of Ucn-1 increases skeletal muscle mass, improves muscle resistance to mechanical stress, and it improves dystrophic muscle structure and function (Reutenauer-Patte et al. 2012).
Interestingly, urocortin isoforms have several effects on the cardiovascular system. The three urocortin peptides promote the vasodilatation of different arteries isolated from human samples or form an animal model (Smani et al. 2011; Wiley and Davenport 2004). These effects implicate the decrease of intracellular Ca2+ concentration ([Ca2+]i) in smooth muscle cells and seem both dependent and independent of the endothelium (Diaz and Smani 2013). Ucn-1 and Ucn-2 have also direct effects on the heart in the absence of any influence of the nervous system. Both isoforms enhance hemodynamics parameters in ex-vivo Langendorff-perfused hearts (Lawrence et al. 2003; Calderon-Sanchez et al. 2009). The evoked positive inotropic and lusitropic actions are due to complex mechanisms involving different kinases signaling pathways and the regulation of [Ca2+]i.
Urocortin peptides have also the ability to protect the heart from ischemia and reperfusion injuries by their improvement of postischemic cardiac performances. Urocortin cardioprotective effects involve a rapid activation of specific targets and are able to reduce necrosis, to enhance cardiac cell survival, and to improve contractility in isolated rat or sheep hearts exposed to ischemia and reperfusion (for review see Diaz and Smani 2013). Urocortin has also other long-lasting cardioprotective effects on gene expression of different end-effector molecules (Calderón-Sánchez et al. 2016). Different mechanisms have been implicated in the cardioprotection afforded either by Ucn-1 or Ucn-2, involving the rapid activation of protective signaling pathways, calcium-independent phospholipase A2 (iPLA2) and protein kinase C epsilon (PKCε), [Ca2+]i handling, or ERK1/2, among others signaling pathway.
Interestingly, independent studies have been conducted in patients with different kinds of heart failure (for review see Adão et al. 2015). These studies show that Ucn-1, Ucn-2, and Ucn-3 enhance cardiac output, reduce peripheral vascular resistance, decrease blood pressure, and it also might regulate renal indices such as creatinine clearance, renin activity, and urine volume.
Altogether, these beneficial effects of urocortin isoforms encourage us to hold a hope and suggest urocortin as a valuable target for the treatment of diseases associated with cardiac dysfunction which are worth further investigations.
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