Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Aquaporin-2 Interaction with Cortisol Modulates its Water Permeability. Perspectives for Corticosteroids Non-genomic Effects

Version 1 : Received: 7 December 2022 / Approved: 9 December 2022 / Online: 9 December 2022 (02:31:09 CET)

A peer-reviewed article of this Preprint also exists.

Mom, R.; Réty, S.; Auguin, D. Cortisol Interaction with Aquaporin-2 Modulates Its Water Permeability: Perspectives for Non-Genomic Effects of Corticosteroids. Int. J. Mol. Sci. 2023, 24, 1499. Mom, R.; Réty, S.; Auguin, D. Cortisol Interaction with Aquaporin-2 Modulates Its Water Permeability: Perspectives for Non-Genomic Effects of Corticosteroids. Int. J. Mol. Sci. 2023, 24, 1499.

Abstract

Aquaporins (AQPs) are water channels widely distributed in living organisms and involved in many pathophysiologies as well as in cell volume regulations (CVR). In the present study, based on the structural homology existing between mineralocorticoids receptors (MR), glucocorticoids receptors (GR), cholesterol consensus motif (CCM) and the extra-cellular vestibules of AQPs, we investigated the binding of corticosteroids on AQP family through in silico molecular dynamics simulations of AQP2 interactions with cortisol. We propose for the first time a putative AQPs corticosteroids binding site (ACBS) and discussed its conservation through structural alignment. Corticosteroids can mediate non-genomic effects, nonetheless, the transduction pathways involved are still misunderstood. Moreover, a growing body of evidence is pointing out toward the existence of a novel membrane receptor mediating part of these rapid corticosteroids effects. Our results suggest that the naturally produced glucocorticoid cortisol inhibits channel water permeability. Based on these results, we propose a detailed description of a putative underlying molecular mechanism. In this process, we also bring new insights on the regulatory function of AQPs extra-cellular loops and on the role of ions in tuning the water permeability. Altogether, this work brings new insights into corticosteroids non-genomic effects through the proposition of AQPs as membrane receptor of this family of regulatory molecules. This original result is the starting point for future investigations to define more in depth and in vivo the validity of this functional model.

Keywords

AQP2; cortisol; corticosteroid; non-genomic effects; molecular dynamics; water permeability

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

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