Dexamethasone, a direct modulator of AQP2 in Meniere s disease.

Abstract

Menieres disease is a chronic illness characterized by intermittent episodes of vertigo associated with fluctuating sensorineural hearing loss, tinnitus and aural pressure. This pathology strongly correlates with a dilatation of the fluid compartment of the endolymph, so-called hydrops. Dexamethasone is one of the therapeutic approaches recommended when conventional antivertigo treatments have failed. Several mechanisms of actions have been hypothesized for the mode of action of dexamethasone such as anti-inflammatory effect or as a regulator of the inner ear water homeostasis. However, none of them have been experimentally confirmed so far. Aquaporins (AQPs) are transmembrane water channels and are hence central in the regulation of trans-cellular water fluxes. In the present study we investigated the hypothesis that dexamethasone could impact water fluxes in the inner ear through direct interaction with AQP2. We addressed this question through molecular dynamics simulations approaches and managed to demonstrate a direct interaction between AQP2 and dexamethasone and its significant impact on the channel water permeability. We also describe the molecular mechanisms involved in dexamethasone binding and in its regulatory action upon AQP2 function. HighlightsO_LIAQP2 water permeability is modulated by dexamethasone at physiological concentrations C_LIO_LIThe interaction impacts water fluxes through a direct interaction with the extra-cellular surface of the aquaporin C_LIO_LIKey interactions implicate conserved residues of the ar/R constriction C_LIO_LINew insights on corticosteroids mode of actions in Menieres disease treatment C_LI