TY - JOUR
T1 - Inhibition of the proton-coupled folate transporter (PCFT-SLC46A1) by bicarbonate and other anions
AU - Zhao, Rongbao
AU - Visentin, Michele
AU - Suadicani, Sylvia O.
AU - Goldman, I. David
PY - 2013/7
Y1 - 2013/7
N2 - The proton-coupled folate transporter (PCFT) plays a key role in intestinal folate absorption, and loss-of-function mutations in the gene encoding this transporter are the molecular basis for hereditary folate malabsorption. Using a stable transfectant with high expression of PCFT, physiologic levels of bicarbonate produced potent and rapidly reversible inhibition of PCFT-mediated transport at neutral pH. Bisulfite and nitrite also inhibited PCFT function at neutral pH, whereas sulfate, nitrate, and phosphate had no impact at all. At weakly acidic pH (6.5), bisulfite and nitrite exhibited much stronger inhibition of PCFT-mediated transport, whereas sulfate and nitrate remained noninhibitory. Inhibition by bisulfite and nitrite at pH6.5 was associatedwith a marked decrease in the influx Vmax and collapse of the transmembrane proton gradient attributed to the diffusion of the protonated forms into these cells. Monocarboxylates such as pyruvate and acetate also collapsed the pH gradient andwere also inhibitory, whereas citrate and glycine neither altered the proton gradient nor inhibited PCFTmediated transport. These observations add another dimension to the unfavorable pH environment for PCFT function in systemic tissues: the presence of high concentrations of bicarbonate.
AB - The proton-coupled folate transporter (PCFT) plays a key role in intestinal folate absorption, and loss-of-function mutations in the gene encoding this transporter are the molecular basis for hereditary folate malabsorption. Using a stable transfectant with high expression of PCFT, physiologic levels of bicarbonate produced potent and rapidly reversible inhibition of PCFT-mediated transport at neutral pH. Bisulfite and nitrite also inhibited PCFT function at neutral pH, whereas sulfate, nitrate, and phosphate had no impact at all. At weakly acidic pH (6.5), bisulfite and nitrite exhibited much stronger inhibition of PCFT-mediated transport, whereas sulfate and nitrate remained noninhibitory. Inhibition by bisulfite and nitrite at pH6.5 was associatedwith a marked decrease in the influx Vmax and collapse of the transmembrane proton gradient attributed to the diffusion of the protonated forms into these cells. Monocarboxylates such as pyruvate and acetate also collapsed the pH gradient andwere also inhibitory, whereas citrate and glycine neither altered the proton gradient nor inhibited PCFTmediated transport. These observations add another dimension to the unfavorable pH environment for PCFT function in systemic tissues: the presence of high concentrations of bicarbonate.
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U2 - 10.1124/mol.113.085605
DO - 10.1124/mol.113.085605
M3 - Article
C2 - 23609145
AN - SCOPUS:84879107962
SN - 0026-895X
VL - 84
SP - 95
EP - 103
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 1
ER -