Molecular characterization of a human cation-Cl- cotransporter (SLC12A8A, CCC9A) that promotes polyamine and amino acid transport.
Cation-Cl- cotransporters (CCCs) belong to a large family of proteins that includes 9 isoforms, two of which have still not been ascribed a transport function (CCC8 and CCC9) while the others are all known to promote Cl(-)-coupled Na+ and/or K+ movement at the cell surface. The CCCs are also included in a larger family termed amino acid-polyamine-organocation carriers (APCs). In contrast to the CCCs, however, polyamine (PA) transporters have thus far been isolated from unicellular species exclusively and do not all belong to the APC family. In this work, we have found that a splice variant of CCC9 (CCC9a) promotes PA-amino acid transport at the surface of HEK-293 cells. We have also found that the influx of PAs in CCC9a-expressing cells is inhibited by pentamidine as well as furosemide, and that it increases further in the presence of specific amino acids but not of Na+, K+, or Cl-. Hence, a group of substrates that are directly transported by CCC9 and the molecular identity of a PA transport system in animal cells may have been uncovered for the first time. These findings are of special interest given that intracellular PAs play a key role in cell proliferation.
Daigle
Nikolas D
ND
Department of Medicine, Nephrology Research Group of the CHUQ-L'Hôtel-Dieu de Québec Institution, Laval University, Québec G1R2J6, Canada.
Carpentier
Gabriel A
GA
Frenette-Cotton
Rachelle
R
Simard
Michael G
MG
Lefoll
Marie-Hélène
MH
Noël
Micheline
M
Caron
Luc
L
Noël
Josette
J
Isenring
Paul
P
D000596:Amino Acids / Q000378:metabolism*; D001692:Biological Transport; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D005665:Furosemide / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D007700:Kinetics; D008935:Mitoguazone / Q000494:pharmacology; D010269:Paraquat / Q000494:pharmacology; D010419:Pentamidine / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D020033:Protein Isoforms; D012964:Sodium / Q000378:metabolism; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000596:Amino Acids; D002712:Chlorides; D011073:Polyamines; D020033:Protein Isoforms; C455505:SLC12A8 protein, human; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D010419:Pentamidine; D005665:Furosemide; D012964:Sodium; D008935:Mitoguazone; D010269:Paraquat; D011188:Potassium