The G Protein-Coupled Receptor UT of the Neuropeptide Urotensin II Displays Structural and Functional Chemokine Features

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.

Oxidative parameters, oxidative DNA damage, and urotensin-II in schizoaffective disorder patients

“…U-II may be an important mediator in the central nervous system by means other than oxidative system. U-II was first isolated from the urophysis of teleost fish, which is an analogue of hypothalamic-pituitary axis and the receptor of U-II was found to be located throughout the central nervous system [24,25]. It has also been shown that U-II and its receptor may be a novel chemokine system that may influence the development of the central nervous system by recent studies [25].…”

“…U-II was first isolated from the urophysis of teleost fish, which is an analogue of hypothalamic-pituitary axis and the receptor of U-II was found to be located throughout the central nervous system [24,25]. It has also been shown that U-II and its receptor may be a novel chemokine system that may influence the development of the central nervous system by recent studies [25]. The modulatory effect of U-II on behavioural, hormonal, oxidative, and inflammatory factors and its newly discovered migration regulatory effect suggest that U-II may play a role in the pathophysiology of psychotic disorders.…”

Urotensin II: an inflammatory cytokine

“…The biological activity of UII must be transduced by UT signaling, so the two are commonly referred to as the UII/UT system. In vivo, the tissue distribution of UT and UII is highly consistent (Castel et al 2017). In most cases, the UII/UT-expressing cells are also highly consistent, showing an autocrine/paracrine regulatory mechanism (Balat et al 2007, Wang et al 2011.…”

“…CFWKYC hexapeptide cyclic conserved portion. The cyclic conserved portion is the main functional region of UII (Castel et al 2017). The human UII gene, also known as UTS2, contains five exons.…”

Multiple-Dose Pharmacokinetics, Pharmacodynamics, and Safety of the Urotensin-II Receptor Antagonist Palosuran in Healthy Male Subjects

“…More recently, U-II and UT receptors have been linked to exert effects on the immune system through involvement in production of cytokines and promotion of immune cell infiltra-DOI: 10.1159/000492936 tion. With the observation of U-II and UT-receptors in numerous cancer cell lines and tumor samples, the urotensinergic could be a new chemokine therapeutic target in pathological situations involving cell chemoattraction [25][26][27][28].…”