Role of AQP9 in transport of monomethyselenic acid and selenite

Abstract

AQP9 is an aquaglyceroporin with a very broad substrate spectrum. In addition to its orthodox nutrient substrates, AQP9 also transports multiple neutral and ionic arsenic species including arsenic trioxide, monomethylarsenous acid (MAsIII) and dimethylarsenic acid (DMAV). Here we discovered a new group of AQP9 substrates which include two clinical relevant selenium species. We showed that AQP9 efficiently transports monomethylselenic acid (MSeA) with a preference for acidic pH, which has been demonstrated in X. laevis oocyte following the overexpression of human AQP9. Specific inhibitors that dissipate transmembrane proton potential or change the transmembrane pH gradient, such as FCCP, valinomycin, and nigericin did not significantly inhibit MSeA uptake, suggesting MSeA transport is not proton coupled. AQP9 was also found to transport ionic selenite and lactate, with much less efficiency compared with MSeA transport. Selenite and lactate uptake via AQP9 is pH gradient dependent and inhibited by FCCP and nigericin, but not valinomycin. The selenite and lactate uptake via AQP9 can be inhibited by different lactate analogs, indicating that their translocation share similar mechanisms. AQP9 transport of MSeA, selenite and lactate is all inhibited by a previously identified AQP9 inhibitor, phloretin, and the AQP9 substrate AsIII. These newly identified AQP9 selenium substrates imply that AQP9 could play a significant role in MSeA uptake and possibly selenite uptake involved with cancer therapy under specific microenvironments.

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei

“…Two trypanocidal bis-phosphonium compounds, CD38 ( Taladriz et al, 2012 ) and AHI43 ( Alkhaldi et al, 2016 ) did inhibit pentamidine uptake (K i 5–10 µM), whereas two related compounds, CDIV31 and AHI15 ( Taladriz et al, 2012 ), did not. Phloretin, which inhibits human AQP9 and AQP3 ( Geng et al, 2017 ), 47 displayed a K i of 1.76 µM for HAPT1/TbAQP2.…”

Differential Expressions of Aquaporin Subtypes in Female Reproductive Tract of Mice

“…AQP9 is a member of the aquaglyceroporin family and shares high homology with AQP3 ( Rojek et al, 2007 ). In addition to water, AQP9 transports not only small uncharged molecules like glycerol, urea, purines, and pyrimidines, but also multiple neutral and ionic arsenic species including arsenic trioxide, monomethylarsenous acid and dimethylarsenic acid ( Geng et al, 2017 ). AQP9 expresses in liver, leukocytes, brain and testis and is important for hepatic glycerol metabolism ( Calamita et al, 2018 ).…”

Aquaglyceroporins: Drug Targets for Metabolic Diseases?

“…In addition, human AQP9 is permeable to two other major methylation products of inorganic arsenic: monomethylarsonic acid (MMA V ) and dimethylarsenic acid (DMA V ) ( McDermott et al, 2010 ). Human AQP9 was also found to be permeable to lactate, ionic selenite and monomethylselenic acid (MSeA) ( Geng et al, 2017 ). MSeA could be used for the prevention and treatment of several cancer types, such as pancreatic cancer ( Wang et al, 2014 ) and lung cancer ( Swede et al, 2003 ), as it induces cell cytotoxicity.…”

“…Due to its permeability to glucogenic glycerol ( Jelen et al, 2011 ; Calamita et al, 2012 ; Geng et al, 2017 ), AQP9 represents an interesting drug target in the pharmacological modulation of gluconeogenesis.…”