Integration of a 'proton antenna' facilitates transport activity of the monocarboxylate transporter MCT4

FEBS J. 2017 Jan;284(1):149-162. doi: 10.1111/febs.13964. Epub 2016 Dec 7.


Monocarboxylate transporters (MCTs) mediate the proton-coupled transport of high-energy metabolites like lactate and pyruvate and are expressed in nearly every mammalian tissue. We have shown previously that transport activity of MCT4 is enhanced by carbonic anhydrase II (CAII), which has been suggested to function as a 'proton antenna' for the transporter. In the present study, we tested whether creation of an endogenous proton antenna by introduction of a cluster of histidine residues into the C-terminal tail of MCT4 (MCT4-6xHis) could facilitate MCT4 transport activity when heterologously expressed in Xenopus oocytes. Our results show that integration of six histidines into the C-terminal tail does indeed increase transport activity of MCT4 to the same extent as did coexpression of MCT4-WT with CAII. Transport activity of MCT4-6xHis could be further enhanced by coexpression with extracellular CAIV, but not with intracellular CAII. Injection of an antibody against the histidine cluster into MCT4-expressing oocytes decreased transport activity of MCT4-6xHis, while leaving activity of MCT4-WT unaltered. Taken together, these findings suggest that transport activity of the proton-coupled monocarboxylate transporter MCT4 can be facilitated by integration of an endogenous proton antenna into the transporter's C-terminal tail.

Keywords: Xenopus oocytes; ion-selective microelectrodes; proton-collecting antenna; transport metabolon.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Biological Transport / drug effects
  • Carbonic Anhydrase II / genetics
  • Carbonic Anhydrase II / metabolism*
  • Carbonic Anhydrase IV / genetics
  • Carbonic Anhydrase IV / metabolism*
  • Gene Expression
  • Histidine / antagonists & inhibitors
  • Histidine / genetics
  • Histidine / metabolism*
  • Lactic Acid / metabolism
  • Microinjections
  • Monocarboxylic Acid Transporters / genetics
  • Monocarboxylic Acid Transporters / metabolism*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Oligopeptides / antagonists & inhibitors
  • Oligopeptides / genetics
  • Oligopeptides / metabolism*
  • Oocytes / cytology
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Protein Engineering
  • Protons*
  • Pyruvic Acid / metabolism
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Xenopus laevis


  • Antibodies, Neutralizing
  • His-His-His-His-His-His
  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • Oligopeptides
  • Protons
  • Recombinant Fusion Proteins
  • Slc16a3 protein, rat
  • Lactic Acid
  • Histidine
  • Pyruvic Acid
  • Carbonic Anhydrase II
  • Carbonic Anhydrase IV
  • CA4 protein, human