Abstract
The urotensinergic system was previously considered as being linked to numerous physiopathological states, including atherosclerosis, heart failure, hypertension, pre-eclampsia, diabetes, renal disease, as well as brain vascular lesions. Thus, it turns out that the actions of the urotensin II (UII)/G protein-coupled receptor UT system in animal models are currently not predictive enough in regard to their effects in human clinical trials and that UII analogs, established to target UT, were not as beneficial as expected in pathological situations. Thus, many questions remain regarding the overall signaling profiles of UT leading to complex involvement in cardiovascular and inflammatory responses as well as cancer. We address the potential UT chemotactic structural and functional definition under an evolutionary angle, by the existence of a common conserved structural feature among chemokine receptorsopioïdergic receptors and UT, i.e., a specific proline position in the transmembrane domain-2 TM2 (P2.58) likely responsible for a kink helical structure that would play a key role in chemokine functions. Even if the last decade was devoted to the elucidation of the cardiovascular control by the urotensinergic system, we also attempt here to discuss the role of UII on inflammation and migration, likely providing a peptide chemokine status for UII. Indeed, our recent work established that activation of UT by a gradient concentration of UII recruits Gαi/o and Gα13 couplings in a spatiotemporal way, controlling key signaling events leading to chemotaxis. We think that this new vision of the urotensinergic system should help considering UT as a chemotactic therapeutic target in pathological situations involving cell chemoattraction.
Highlights
The urotensinergic system was previously considered as being linked to numerous pathophysiological states, including atherosclerosis, heart failure, hypertension, pre-eclampsia, diabetes, renal disease, as well as brain vascular lesions
The neuropeptide urotensin II (UII) is composed of 11 amino acids in primates to 17 amino acids in the mouse and shows remarkable conservation of the C-terminal CFWKYC hexapeptide portion formed by the covalent disulfide bridge (Table 1) during evolution, suggesting a crucial importance of the cycle in biological activity
UII has been characterized in a single species of invertebrates, the Aplysia californica [6], in a form composed of 20 amino acids and whose cyclic hexapeptide differs from vertebrates by only two residues (F→L and Y→V) [7]
Summary
The urotensinergic system was previously considered as being linked to numerous pathophysiological states, including atherosclerosis, heart failure, hypertension, pre-eclampsia, diabetes, renal disease, as well as brain vascular lesions. Validation of urotensin II (UII) receptor (UT) antagonism in cell lines expressing rat or human UT, observations in animal models, and even clinical results were not as beneficial as expected, probably because of the complex effects of the urotensinergic system depending on the vascular bed, the studied animal species, and/or
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