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

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.

Keywords: aquaporin (AQP); facilitated diffusion; fluid; membranes; osmosis; secretion; signaling; water.

Figure 1

AQP distribution in the human body. Expression of AQP paralogs in the (a) brain, (b) blood–brain barrier, (c) eye, (d) exocrine glands, (e) inner ear, (f) cardiovascular system, (g) spine, (h) heart, (i) respiratory tract (trachea and lung; inset showing alveoli), (j) skeletal muscle, (k) pancreas, (l) liver, (m) gastrointestinal tract, (n) kidney, (o) skin (inset showing adipose tissue), and (p) female as well as (q) male reproductive tracts. This summary is not comprehensive; minor AQP subtypes are omitted for clarity. Bold text is used to highlight the major AQPs studied in the selected tissues. Created with BioRender.com; adapted from Day et al., 2014 [12].

Figure 2

Structural biology of the AQP family. (A) The signature fold of the AQP family consists of six transmembrane helices and two helix-forming re-entrant loops containing the signature NPA motif. (B,C) Water transport and selectivity is facilitated by the NPA motifs (green) found at the interface of the two helical re-entrant loops (red) and the aromatic/arginine selectivity filter (blue). Water molecules (a single water oxygen at the selectivity filter is indicated by a purple sphere) traverse the pore in single-file. (D–F) The central pore formed at the fourfold axis of AQP1 contains two rings of bulky hydrophobic residues (orange) that prevent pore hydration in the absence of a cGMP signal. cGMP binding at loop D (green) activates the ion channel. Created with Biorender.com.

Figure 3

Functional roles of AQPs. (A) Fluid homeostasis and secretion: In the kidney, AQP1 regulates water reabsorption in the proximal tubules, while AQP2–4 are involved in urine concentration. In the central nervous system (CNS), AQP1 is involved in cerebrospinal fluid (CSF) production in the choroid plexus. In the lungs, AQPs facilitate transendothelial and transepithelial water flow. (B) Signal transduction and sensor function: AQP4 is involved in skeletal muscle contraction and viability. In the spinal cord, AQP1 is thought to contribute to pain processing and promote axonal growth as well as the regeneration of dorsal root ganglia (DRG). In the inner ear, AQPs are involved in balance and hearing. In the eye, AQP0 facilitates the structural integrity and transparency of the lens. (C) Defense, protection, and support: AQP4 is involved in blood–brain barrier (BBB) integrity, astrocyte plasticity, glial scar formation, and cerebral waste clearance. AQP3 supports skin hydration and wound healing. AQP1, 3, 5, 7, and 9 are involved in immune cell activation and pathogen elimination (phagocytosis). AQP7, 9, and 10 are involved in the glycerol transport that supports energy metabolism. (D) Cell motility: AQP1, 4, 5, and 9 are polarized at the leading edge of migrating cells and are thought to promote the cellular migration stages of polarization, protrusion, adhesion, and retraction. Additionally, AQP1, 3, 4, and 9 are assumed to enhance the degradation of the extracellular matrix (ECM). Created with BioRender.com.