br Acknowledgments br Introduction br

Acknowledgments
Introduction
Endothelin receptors Shortly after the discovery of ET‐1, two types of seven transmembrane G protein‐coupled receptors were cloned called endothelin receptor A (ETA) (Arai et al., 1990) and ETB (Sakurai et al., 1990). The affinity of the ETA receptor for ET-3 is less than its affinity for ET-1 and ET-2, while the ETB receptor binds the three endothelins with the same affinity. No specific agonist for the ETA receptor and only two ETB receptor agonists, sarafotoxin 6c and IRL1620, are actually available (Watts, 2010). However, the study of each receptor\'s role has been facilitated with the development of several selective antagonists for both ETA receptors (e.g. atrasentan) (Jae et al., 2001) and ETB receptors (e.g. BQ‐788) (Ishikawa et al., 1994) and dual antagonists, like bosentan (Clozel et al., 1994) or more recently developed macitentan (Iglarz et al., 2008). ET‐1 has a similar affinity for both receptors (Arai et al., 1990, Sakurai et al., 1990). The intracellular pathways installed after ET‐1-induced ETA and ETB receptors activation involve the Gq, Gs and Gi small G proteins leading to stimulation of phospholipase C (PLC). The consecutive production of inositol triphosphate (IP3) and diacylglycerol (DAG) increases the concentration of intracellular calcium (Ca2+). Ca2+ is recruited from the reticulum by activation of the inositol triphosphate (IP3) receptor and external Ca2+ influx is increased by opening of the Ca2+ Anhydrotetracycline hydrochloride on the cellular membrane (Simonson and Dunn, 1990). ETA and ETB receptors can have synergetic or opposing effects depending on cell type, tissue type or physiological situation. The ETA receptor shows an atypical long-lasting agonist-induced effect because ET-1 dissociates particularly slowly from its receptors. Based on a two-state two-site model, it has been proposed that ET-1 and ETA receptor antagonists bind to distinct sites and antagonists therefore prevent the binding of ET-1 but may reduce only partly the actions of already bound ET-1 (De Mey et al., 2011). After activation, the ETB receptor is internalized and targeted to the lysosome (Bremnes et al., 2000). ETB receptor selective (Strachan et al., 1999), non-selective (Iglarz et al., 2008) and in a much lesser extent selective ETA receptor antagonists (Opgenorth et al., 2000) elevate the serum level of ET-1. Together these data reveal the predominant role of the ETB receptors for the clearance of circulating ET-1, which occurs mainly in the lungs and the kidneys (Johnstrom et al., 2005). The presence of homo- and heterodimers of the endothelin receptors has been recently observed in vitro and possibly counts for the complexity of ET-1 responses. The types of dimers (ETA/ETA, ETA/ETB, or ETB/ETB) are characterized by different binding density (Evans and Walker, 2008). Moreover, the functional response is different whether homo- or heterodimers are formed: the binding of ET-1 to homodimers induces a transient elevation in Ca2+ concentration, while the response mediated by heterodimers lasts for several minutes (Evans and Walker, 2008). In pulmonary arteries of rats, Sauvageau et al. (2009) could demonstrate by co-immunoprecipitation a heterodimerization of the two endothelin receptors. Furthermore, endothelin receptors could possibly form dimers with other receptors: Zeng et al. proposed that the loss of the dopamine receptor function in renal tubule of hypertensive rats is due to impaired binding to the ETB receptor (Zeng et al., 2008a). The functional relevance of these observations and particularly how pharmacological observations could be explained by the formation of dimers was recently discussed elsewhere (Watts, 2010). Finally, a molecule could represent an alternative target of ET-1: a dual ET-1/angiotensin II receptor called DEAR (Ruiz-Opazo et al., 1998).
ET-1 in the vasculature
ET-1 in the heart
ET-1 in the kidney
Conclusion ET-1 is a multifunctional hormone with complex effects on the renal, cardiac and vascular physiology. ET-1 is a strong vasoconstrictor while the activation of the endothelial ETB receptor induces the production of vasodilator NO. ET-1 has positive inotropic feature but has been shown to reduce contractility in disease state. ET-1 is overexpressed in the failing heart but may prevent apoptosis and restore cardiac function in stress situation. In the kidney, ET-1 is a diuretic and natriuretic hormone in which it antagonizes its vascular effect on blood pressure. The accumulating research in the endothelin field reveals further the complexity of this system but provides knowledge, which will most probably end up in the development of novel therapies.