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

ABSTRACT: 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 co-transport. 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 120 mV. 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(VNAT)s that could replace the missing NHEs. We review published evidence in support of this hypothesis and speculate about broader functions of NHE(VNAT)s.

SUBMITTER: Harvey WR

PROVIDER: S-EPMC2727077 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Harvey William R WR Boudko Dmitri Y DY Rheault Mark R MR Okech Bernard A BA

The Journal of experimental biology 20090201 Pt 3

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 ...[more]

PMID: 19151209

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Project description:Neurotransmitter/Na(+) symporters (NSSs) terminate neuronal signalling by recapturing neurotransmitter released into the synapse in a co-transport (symport) mechanism driven by the Na(+) electrochemical gradient. NSSs for dopamine, noradrenaline and serotonin are targeted by the psychostimulants cocaine and amphetamine, as well as by antidepressants. The crystal structure of LeuT, a prokaryotic NSS homologue, revealed an occluded conformation in which a leucine (Leu) and two Na(+) are bound deep within the protein. This structure has been the basis for extensive structural and computational exploration of the functional mechanisms of proteins with a LeuT-like fold. Subsequently, an 'outward-open' conformation was determined in the presence of the inhibitor tryptophan, and the Na(+)-dependent formation of a dynamic outward-facing intermediate was identified using electron paramagnetic resonance spectroscopy. In addition, single-molecule fluorescence resonance energy transfer imaging has been used to reveal reversible transitions to an inward-open LeuT conformation, which involve the movement of transmembrane helix TM1a away from the transmembrane helical bundle. We investigated how substrate binding is coupled to structural transitions in LeuT during Na(+)-coupled transport. Here we report a process whereby substrate binding from the extracellular side of LeuT facilitates intracellular gate opening and substrate release at the intracellular face of the protein. In the presence of alanine, a substrate that is transported ?10-fold faster than leucine, we observed alanine-induced dynamics in the intracellular gate region of LeuT that directly correlate with transport efficiency. Collectively, our data reveal functionally relevant and previously hidden aspects of the NSS transport mechanism that emphasize the functional importance of a second substrate (S2) binding site within the extracellular vestibule. Substrate binding in this S2 site appears to act cooperatively with the primary substrate (S1) binding site to control intracellular gating more than 30?Å away, in a manner that allows the Na(+) gradient to power the transport mechanism.

Dataset Information

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

Publications

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

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