Aquaporins: important but elusive drug targets

Abstract

The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators.

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…Given the role of AQP4 in K + and water homeostasis, it seems rational to develop AQP4 modulators as drugs against diseases involving brain edema (King, Yasui, & Agre, 2000). Unfortunately, limited progress has been made in AQP4‐targeted therapeutics (Verkman, Anderson, & Papadopoulos, 2014). This is partly due to the lack of robust assays of AQP4 activity.…”

“…This is partly due to the lack of robust assays of AQP4 activity. The small size of the functional AQP4 monomer and its very small pore diameter, which prevents the access of conventional small molecules, translates to poor “druggability” (Verkman et al, 2014). As AQP4 are simple passive pores, they lack sophisticated gating and transport mechanisms suitable for targeting with small molecules.…”

“…As AQP4 are simple passive pores, they lack sophisticated gating and transport mechanisms suitable for targeting with small molecules. Furthermore, mutations in the extracellular and cytoplasmic domains of AQP4 generally have little effect on water permeability through the channel, which suggests that the binding of an inhibitor has to occur deep in the narrow pore to physically prevent water conduction (Papadopoulos and Verkman, 2013; Verkman et al, 2014). Nevertheless, further large‐scale screening of random and computationally biased libraries in search of AQP4 blockers is warranted.…”

TRPV4-AQP4 interactions ‘turbocharge’ astroglial sensitivity to small osmotic gradients

“…1 AQP4 ¡/¡ mice are protected from certain types of mechanical stress including pathological water accumulation in edema yet AQP4 may not always be an appropriate target given that loss-of-function mutations and AQP4 ablation increase susceptibility to seizures. 1 Our recent study in retinal glial cells suggests an alternative might be to instead target the mechanism that transduces swelling into downstream cation signals. 2 Specifically, we identified the reciprocal interaction between a nonselective cation channel, TRPV4 (transient receptor potential isoform 4) and AQP4 as the key to astroglial swelling, volume regulation and reorganization of downstream signaling pathways in retinal Muller cells.…”

“…2,4,5 We hypothesize that coordination of activitydependent ionic/water fluxes at the blood-retina barrier critically depends on functional interactions between endfoot TRPV4, AQP4 and Kir4.1 channels. This osmoregulatory complex links changes in glial water permeability, K C uptake, ATP release and Ca 2C homeostasis that occur in response to during neuronal firing, 1,8 to downstream modulation of Aqp4 and Kcnj10 and astroglial function by maintaining the steady-state 'osmo-tensile' homeostasis. In the presence of prolonged osmotic stress or pathological circumstances (such as diabetes, traumatic ocular injury or glaucoma), however, TRPV4-AQP4 interactions associated with excessive swelling of CNS astroglia 'turbo-charge' inflammatory remodeling through deranged Ca 2C signaling, reactive gliosis and macular or brain edema.…”