Human Aquaporins: Functional Diversity and Potential Roles in Infectious and Non-infectious Diseases

Abstract

Aquaporins (AQPs) are integral membrane proteins and found in all living organisms from bacteria to human. AQPs mainly involved in the transmembrane diffusion of water as well as various small solutes in a bidirectional manner are widely distributed in various human tissues. Human contains 13 AQPs (AQP0-AQP12) which are divided into three sub-classes namely orthodox aquaporin (AQP0, 1, 2, 4, 5, 6, and 8), aquaglyceroporin (AQP3, 7, 9, and 10) and super or unorthodox aquaporin (AQP11 and 12) based on their pore selectivity. Human AQPs are functionally diverse, which are involved in wide variety of non-infectious diseases including cancer, renal dysfunction, neurological disorder, epilepsy, skin disease, metabolic syndrome, and even cardiac diseases. However, the association of AQPs with infectious diseases has not been fully evaluated. Several studies have unveiled that AQPs can be regulated by microbial and parasitic infections that suggest their involvement in microbial pathogenesis, inflammation-associated responses and AQP-mediated cell water homeostasis. This review mainly aims to shed light on the involvement of AQPs in infectious and non-infectious diseases and potential AQPs-target modulators. Furthermore, AQP structures, tissue-specific distributions and their physiological relevance, functional diversity and regulations have been discussed. Altogether, this review would be useful for further investigation of AQPs as a potential therapeutic target for treatment of infectious as well as non-infectious diseases.

Keywords: aquaporins and infectious diseases; drug targets; functional regulation; human aquaporins; water homeostasis.

FIGURE 1

Infection route, spreading and shedding at different organs of the body and tissue-specific distribution of AQPs. The roles of AQPs in non-infectious diseases such as different cancers and tumors, cerebral edema and ischemic stroke, obesity, renal and skin diseases, and cataracts have been widely studied. At least 10 AQPs of different organs are associated with bacterial, viral, and parasitic infections. Expressions of AQPs in infectious diseases are summarized in Table 2 of the current review.

FIGURE 2

The structure of AQP monomer and homotetramers. A schematic representation of the general structures of AQP is shown (A–C). (A) Each AQP monomer has six transmembrane domains (1–6) spanning the plasma membrane, which are connected with five loops (A–E). (B) Two conserved NPA motifs in loops B and E are juxtaposed oppositely to form the channel through which molecules are passed. (C) Each AQP monomer contains independent pore (shown as blue arrow) and the monomers are assembled as tetramers to form a central pore (shown as green arrow). (D) Side view of the structure of the human AQP1 monomer, which shows six transmembrane α-helices (TM1-6) including pseudo TM (LE and LB) that are connected with five different loops (A–E). (E) The top view of the human AQP1 is shown. The residues (F56, H180, C189, and Arg195) in the ar/R constriction and two NPA motifs (yellow and cyan) are shown in sticks. (F) The top view of the AQP homotetramers with filled amino acid residues is shown. The pore of each monomer and the central pore of the homotetramers are shown as white circles.