Abstract
The urotensinergic system plays central roles in the physiological regulation of major mammalian organ systems, including the cardiovascular system. As a matter of fact, this system has been linked to numerous pathophysiological states including atherosclerosis, heart failure, hypertension, diabetes as well as psychological, and neurological disorders. The delineation of the (patho)physiological roles of the urotensinergic system has been hampered by the absence of potent and selective antagonists for the urotensin II-receptor (UT). Thus, a more precise definition of the molecular functioning of the urotensinergic system, in normal conditions as well as in a pathological state is still critically needed. The recent discovery of nuclear UT within cardiomyocytes has highlighted the cellular complexity of this system and suggested that UT-associated biological responses are not only initiated at the cell surface but may result from the integration of extracellular and intracellular signaling pathways. Thus, such nuclear-localized receptors, regulating distinct signaling pathways, may represent new therapeutic targets. With the recent observation that urotensin II (UII) and urotensin II-related peptide (URP) exert different biological effects and the postulate that they could also have distinct pathophysiological roles in hypertension, it appears crucial to reassess the recognition process involving UII and URP with UT, and to push forward the development of new analogs of the UT system aimed at discriminating UII- and URP-mediated biological activities. The recent development of such compounds, i.e. urocontrin A and rUII(1–7), is certainly useful to decipher the specific roles of UII and URP in vitro and in vivo. Altogether, these studies, which provide important information regarding the pharmacology of the urotensinergic system and the conformational requirements for binding and activation, will ultimately lead to the development of potent and selective drugs.
Highlights
THE UROTENSINERGIC SYSTEM During the last decade, the urotensinergic system has drawn the attention of the scientific community due to its marked involvement in various pathological states including cardiovascular diseases
The present review focuses on the latest findings about the urotensinergic system in terms of receptor localization and pharmacology as well as receptor activation with the conception of new urotensinergic ligands aimed at discriminating urotensin II (UII)- and/or urotensin II-related peptide (URP)-mediated biological actions
URP, lacking this N-terminal portion and characterized by the presence of an intracyclic γ-turn (Chatenet et al, 2004), would bind urotensin II receptor (UT) in a slightly different manner; triggering a slightly different subset of signaling pathways. These observations have clearly highlighted the crucial need to reassess the development of pan UT antagonists, i.e. blocking UII- and URP-mediated receptor activation, and to develop new analogs of the urotensinergic system aimed at discriminating UII- or URP-mediated biological activities
Summary
Loops (Douglas et al, 2000), this protein possesses a palmitoylation site located in the C-terminal segment of the rodent isoform that is not present in the human isoform (Figure 3). In various peripheral organs including the cardiovascular system, kidneys, bladder, pancreas, and adrenal gland (Figure 2) (Vaudry et al, 2010). The urotensinergic system plays a seminal role in the physiological regulation of major mammalian organ systems, including the cardiovascular system (Vaudry et al, 2010). The present review focuses on the latest findings about the urotensinergic system in terms of receptor localization and pharmacology as well as receptor activation with the conception of new urotensinergic ligands aimed at discriminating UII- and/or URP-mediated biological actions
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