Our understanding of the movement of water through cell membranes has been greatly advanced by the discovery of a family of water-specific, membrane-channel proteins - the aquaporins. These proteins are present in organisms at all levels of life, and their unique permeability characteristics and distribution in numerous tissues indicate diverse roles in the regulation of water homeostasis. The recognition of aquaporins has stimulated a reconsideration of membrane water permeability by investigators across a wide range of disciplines.

Data availabilityAll data presented in this manuscript are available from the corresponding author upon reasonable request. Bulk tumour cell RNA sequencing has been deposited at the Gene Expression Omnibus (GEO) under accession number https://www.ncbi.nlm.nih.gov/geo/ query/acc.cgi?acc=GSE110708. Single-cell RNA sequencing of tumour cells were also deposited at the GEO under accession numberhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE110746.

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Although water is the major component of all biological £uids, the molecular pathways for water transport across cell membranes eluded identi¢cation until the discovery of the aquaporin family of water channels. The atomic structure of mammalian AQP1 illustrates how this family of proteins is freely permeated by water but not protons (hydronium ions, H 3 O + ). De¢nition of the subcellular sites of expression predicted their physiological functions and potential clinical disorders. Analysis of several human disease states has con¢rmed that aquaporins are involved in multiple di¡erent illnesses including abnormalities of kidney function, loss of vision, onset of brain edema, starvation, and arsenic toxicity. BackgroundWater is the major component of all human cells and tissues, and the same is true for all other vertebrates, invertebrates, unicellular organisms, and plants. The plasma membrane is the major barrier to the movement of water between cells, but identi¢cation of the molecular pathways by which water is absorbed and released from cells remained unknown until long after most classes of membrane transport proteins. This is surprising, since the phenomenon of cell membrane water permeability had been debated for decades by physiologists and biophysicists. It was agreed by most scientists that water passes through biological membranes by simple di¡u-sion through the lipid bilayer.Based upon indirect observations, a small number of scientists argued that specialized water-selective pores are necessary to explain the high water permeability of red blood cells and renal tubules [1]. Moreover, the water permeability of these tissues could be reversibly inhibited by mercuric ions [2], and the activation energy was similar to di¡usion of water in bulk solution, V5 kcal/mol. In addition, specialized tissues such as mammalian collecting duct or amphibian bladder were known to exhibit £uctuations in water transport regulated by the antidiuretic hormone, vasopressin. Nevertheless, water channel proponents were unable to convince skeptics, since all attempts to isolate or clone molecular water channel proteins had failed, and no mechanism explained the passage of water (H 2 O) without passage of protons (H 3 O þ , hydronium ions). Discovery of aquaporinsThe discovery of a 28 kDa integral membrane protein in red cells and renal tubules [3] ended the controversies about the possible existence of molecular water channels. The protein now known as AQP1 was ¢rst puri¢ed from red cell membranes and found to exist as a tetramer with intracellular N-and C-termini^an organization similar to several ion channel proteins [4]. The primary sequence of the cDNA revealed two tandem repeats each containing three bilayer-spanning K-helices [5]. The loops connecting the second and third transmembrane segments in each repeat contained several highly conserved residues and the signature motif, asparagine-proline-alanine (NPA). The genetics database at that time included a few homologous proteins from a curious assortment of so...