NHE_VNAT: An H⁺ V-ATPase electrically coupled to a Na⁺:nutrient amino acid transporter (NAT) forms an Na ⁺/H⁺ exchanger (NHE)

Glycolysis, the citric acid cycle and other metabolic pathways of living organisms generate potentially toxic acids within all cells. One ubiquitous mechanism for ridding cells of the acids is to expel H⁺ in exchange for extracellular Na⁺, mediated by electroneutral transporters called Na⁺/H⁺ exchangers (NHEs) that are driven by Na ⁺ concentration gradients. The exchange must be important because the human genome contains 10 NHEs along with two Na⁺/H⁺ antiporters (NHAs). By contrast, the genomes of two principal disease vector mosquitoes, Anopheles gambiae and Aedes aegypti, contain only three NHEs along with the two NHAs. This shortfall may be explained by the presence of seven nutrient amino acid transporters (NATs) in the mosquito genomes. NATs transport Na⁺ stoichiometrically linked to an amino acid into the cells by a process called symport or cotransport. Three of the mosquito NATs and two caterpillar NATs have previously been investigated after heterologous expression in Xenopus laevis oocytes and were found to be voltage driven (electrophoretic). Moreover, the NATs are present in the same membrane as the H⁺ V-ATPase, which generates membrane potentials as high as 120mV. We review evidence that the H⁺ V-ATPase moves H⁺ out of the cells and the resulting membrane potential (V_m) drives Na⁺ linked to an amino acid into the cells via a NAT. The H⁺ efflux by the V-ATPase and Na⁺ influx by the NAT comprise the same ion exchange as that mediated by an NHE; so the V and NAT working together constitute an NHE that we call NHE_VNAT. As the H⁺ V-ATPase is widely distributed in mosquito epithelial cells and there are seven NATs in the mosquito genomes, there are potentially seven NHE_VNATs that could replace the missing NHEs. We review published evidence in support of this hypothesis and speculate about broader functions of NHE_VNATs.