Recent breakthroughs and future directions in drugging aquaporins

Abstract

Aquaporins facilitate the passive transport of water, solutes, or ions across biological membranes. They are implicated in diverse pathologies including brain edema following stroke or trauma, epilepsy, cancer cell migration and tumor angiogenesis, metabolic disorders, and inflammation. Despite this, there is no aquaporin-targeted drug in the clinic and aquaporins have been perceived to be intrinsically nondruggable targets. Here we challenge this idea, as viable routes to inhibition of aquaporin function have recently been identified, including targeting their regulation or their roles as channels for unexpected substrates. Identifying new drug development frameworks for conditions associated with disrupted water and solute homeostasis will meet the urgent, unmet clinical need of millions of patients for whom no pharmacological interventions are available.

Signaling Mechanisms and Pharmacological Modulators Governing Diverse Aquaporin Functions in Human Health and Disease

“…No ion channel function has yet been detected for AQP4 and AQP5 [14], though it is possible that the key stimuli remain to be identified, a concept to be considered for any AQPs that appear to be nonfunctional in experimental assays. When a multiple-sequence alignment analysis is run for human AQPs combined with known non-mammalian AQP ion channels, AQP8 falls on a distant branch of the orthodox group alongside the soybean AQP channel nodulin 26, which conducts water, glycerol, ammonia, and ions [1,15,16]. Although AQP8 in other alignments has been assigned to the 'super-aquaporin' group with AQP11 and AQP12 [17], its capacity for conducting ammonia [18] presents an interesting similarity with nodulin 26.…”

“…Diffusible signaling molecules such as cAMP, cGMP, Ca 2+ , and downstream protein kinases mediate the complex regulation of AQP channel activities, controlling adaptive increases or decreases in functional transport properties and adjusting levels of expression [1]. cAMP and cGMP are involved in numerous biological mechanisms, such as cell growth, differentiation and adhesion, hormone and neuronal signaling, as well as in the regulation of protein kinases, phosphodiesterases, and cyclic-nucleotide-gated ion channels [498][499][500][501][502][503].…”

“…Providing capacity for rapid modifications of membrane physiology by governing channel function, post-translational mechanisms include direct binding and phosphorylation [1]. Cyclic nucleotides can modulate AQPs by direct interaction with a gating domain or by the activation of associated protein kinases, in turn altering the AQP channel via phosphorylation.…”

“…Aquaporins (AQPs) have diverse roles in mammals, ranging from fluid homeostasis, glandular secretions, barrier function, immunity and inflammation, cell migration, and angiogenesis to signal transduction and sensation. It is now clear that AQP functions are more complex than simply mediating the passive flow of water across biological membranes [1]. Understanding their underlying regulatory mechanisms along with the discovery and development of small-molecule AQP inhibitors for use in research and therapeutic development is expected to lead to new insights into the basic biology of and novel treatments for the wide range of AQP-associated disorders.…”

Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells

“…Our finding that AURKA is involved in the control of AQP2 adds another example to the repertoire of AURKA’s non-mitotic functions and supports the notion that AURKA exerts physiological roles outside of the mitotic context. Moreover, the discovery of AURKA inhibitors for interfering with the AQP2 trafficking expands the toolbox of inhibitors that directly interfere with vasopressin-mediated water transport [ 87 ]. The discovery of novel inhibitors of the redistribution of AQP2 also strengthens arguments that modulating the localization of an aquaporin for therapeutic reasons is feasible.…”