Molecular mechanisms governing aquaporin relocalisation

Abstract

The aquaporins (AQPs) form a family of integral membrane proteins that facilitate the movement of water across biological membrane by osmosis, as well as facilitating the diffusion of small polar solutes. AQPs have been recognised as drug targets for a variety of disorders associated with disrupted water or solute transport, including brain oedema following stroke or trauma, epilepsy, cancer cell migration and tumour angiogenesis, metabolic disorders, and inflammation. Despite this, drug discovery for AQPs has made little progress due to a lack of reproducible high-throughput assays and difficulties with the druggability of AQP proteins. However, recent studies have suggested that targetting the trafficking of AQP proteins to the plasma membrane is a viable alternative drug target to direct inhibition of the water-conducting pore. Here we review the literature on the trafficking of mammalian AQPs with a view to highlighting potential new drug targets for a variety of conditions associated with disrupted water and solute homeostasis.

Keywords: AQP; Aquaporin; Membrane trafficking; Osmosis.

Graphical abstract

Fig. 1

Schematic overview of aquaporin regulation. Some plant AQPs are regulated by gating such as (a) SoPIP2;1 where low pH causes protonation of His193 leading to conformational changes and pore occlusion on the intracellular side (open structure at pH 8 PDB ID: 2B5F, closed at pH 6 PDB ID: 4IA4). However, gating has only been reported for (b) mammalian AQP0 through calmodulin binding (PDB 3J41), which occludes the pore. The main regulatory mechanism for mammalian AQPs (represented by AQP4, PDB ID: 3GD8) is (c) via trafficking to and from the plasma membrane. After protein biosynthesis, AQPs are inserted into intracellular vesicles which transfer them to the plasma membrane. A population of intracellular vesicular pools also remains in the cytoplasm, which can be triggered to increase AQP membrane abundance, typically via calmodulin- and phosphorylation-dependent mechanisms. Triggers can be hormonal (e.g. vasopressin-induced localisation of AQP2 to the apical membrane of kidney collecting duct cells, V2R PDB ID: 7KH0) or environmental (e.g. hypoxia-induced localisation of AQP4 to the astrocyte plasma membrane). Internalisation through clathrin-dependent and clathrin-independent (such as caveolae) pathways reduce cell surface abundance via incompletely understood pathways. In addition, some AQPs are released into the extra-cellular space in extracellular vesicles.