Cationic pathway of pH regulation in larvae of Anopheles gambiae

Bernard A. Okech, Dmitri Y. Boudko, Paul J. Linser, William R. Harvey

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Anopheles gambiae larvae (Diptera: Culicidae) live in freshwater with low Na+ concentrations yet they use Na+ for alkalinization of the alimentary canal, for electrophoretic amino acid uptake and for nerve function. The metabolic pathway by which larvae accomplish these functions has anionic and cationic components that interact and allow the larva to conserve Na+ while excreting H+ and HCO3-. The anionic pathway consists of a metabolic CO2 diffusion process, carbonic anhydrase and Cl-/HCO3- exchangers; it provides weak HCO3- and weaker CO3 2- anions to the lumen. The cationic pathway consists of H + V-ATPases and Na+/H+ antiporters (NHAs), Na+/K+ P-ATPases and Na+/H+ exchangers (NHEs) along with several (Na+ or K+):amino acid+/- symporters, a.k.a. nutrient amino acid transporters (NATs). This paper considers the cationic pathway, which provides the strong Na + or K+ cations that alkalinize the lumen in anterior midgut then removes them and restores a lower pH in posterior midgut. A key member of the cationic pathway is a Na+/H+ antiporter, which was cloned recently from Anopheles gambiae larvae, localized strategically in plasma membranes of the alimentary canal and named AgNHA1 based upon its phylogeny. A phylogenetic comparison of all cloned NHAs and NHEs revealed that AgNHA1 is the first metazoan NHA to be cloned and localized and that it is in the same clade as electrophoretic prokaryotic NHAs that are driven by the electrogenic H+ F-ATPase. Like prokaryotic NHAs, AgNHA1 is thought to be electrophoretic and to be driven by the electrogenic H+ V-ATPase. Both AgNHA1 and alkalophilic bacterial NHAs face highly alkaline environments; to alkalinize the larva mosquito midgut lumen, AgNHA1, like the bacterial NHAs, would have to move nH+ inwardly and Na+ outwardly. Perhaps the alkaline environment that led to the evolution of electrophoretic prokaryotic NHAs also led to the evolution of an electrophoretic AgNHA1 in mosquito larvae. In support of this hypothesis, antibodies to both AgNHA1 and H+ V-ATPase label the same membranes in An. gambiae larvae. The localization of H+ V-ATPase together with (Na+ or K +):amino acid+/- symporter, AgNAT8, on the same apical membrane in posterior midgut cells constitutes the functional equivalent of an NHE that lowers the pH in the posterior midgut lumen. All NATs characterized to date are Na+ or K+ symporters so the deduction is likely to have wide application. The deduced colocalization of H+ V-ATPase, AgNHA1 and AgNAT8, on this membrane forms a pathway for local cycling of H + and Na+ in posterior midgut. The local H+ cycle would prevent unchecked acidification of the lumen while the local Na + cycle would regulate pH and support Na+:amino acid +/- symport. Meanwhile, a long-range Na+ cycle first transfers Na+ from the blood to gastric caeca and anterior midgut lumen where it initiates alkalinization and then returns Na+ from the rectal lumen to the blood, where it prevents loss of Na+ during H+ and HCO3- excretion. The localization of H+ V-ATPase and Na+/K+-ATPase in An. gambiae larvae parallels that reported for Aedes aegypti larvae. The deduced colocalization of the two ATPases along with NHA and NAT in the alimentary canal constitutes a cationic pathway for Na+-conserving midgut alkalinization and de-alkalinization which has never been reported before.

Original languageEnglish
Pages (from-to)957-968
Number of pages12
JournalJournal of Experimental Biology
Issue number6
StatePublished - Mar 2008
Externally publishedYes


  • (Na or K ):amino acid symporter
  • AgNAT8
  • AgNHA1
  • Cation exchanger
  • H V-ATPase
  • NAT
  • NHA
  • NHE
  • Na/K P-ATPase
  • Nutrient amino acid transporter
  • Proton pump
  • Sodium pump


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