Abstract
The aquaporins (AQPs) are a family of small integral membrane proteins that facilitate the bidirectional transport of water across biological membranes in response to osmotic pressure gradients as well as enable the transmembrane diffusion of small neutral solutes (such as urea, glycerol, and hydrogen peroxide) and ions. AQPs are expressed throughout the human body. Here, we review their key roles in fluid homeostasis, glandular secretions, signal transduction and sensation, barrier function, immunity and inflammation, cell migration, and angiogenesis. Evidence from a wide variety of studies now supports a view of the functions of AQPs being much more complex than simply mediating the passive flow of water across biological membranes. The discovery and development of small-molecule AQP inhibitors for research use and therapeutic development will lead to new insights into the basic biology of and novel treatments for the wide range of AQP-associated disorders.
Highlights
AQP8 is expressed in the inner membrane of mitochondria and involved in H2 O2 transport linked with the accumulation of reactive oxygen species (ROS) [52], revealing an unexpected breadth of physiologically important roles for AQPs across phyla [13,56] and highlighting many gaps in our knowledge that are yet to be addressed
Tight regulation of central nervous system (CNS) water content is fundamental for the proper functioning of the brain, which is exquisitely sensitive to increased intracranial pressure (ICP) [106]
The aqp1 gene promoter contains a consensus HIF-1α binding motif [486]; AQP1 mRNA and protein levels are elevated under conditions of low oxygen [322,412,487,488], supporting the presumption that AQP1 activity can be regulated by the interplay of growth factors within the tumor microenvironment [489,490]
Summary
The essential role of membrane intrinsic protein channels in the regulation of water transport and homeostasis was discovered in 1986 [2,3]. AQP0 was the first mammalian water channel suggested to mediate conductand glycerol-permeable subtypes, with a third poorly understood ‘super’an or ion ‘subcellular’. The subsequent identification of other members of the AQP family as dual water and ion channels has added the mammalian water channel AQP6, the insect water channel Drosophila big brain (DmBIB), and plant membrane intrinsic proteins such as the Arabidopsis. AQP0 was the first mammalian water channel suggested to mediate an ion conductance, in addition to its function as a water channel [19,20]. AQP10 s function as a gated ion channel was proposed in 1996 [21], and has since been refined to clarify that AQP1 activation occurs via the direct binding of cyclic guanosine monophosphate (cGMP) [22,23,24]. This should not be compatible with the transport of water, alternative barrier sites have been proposed [30]
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