Orphan transporter SLC6A18 is renal neutral amino acid transporter B0AT3.
The orphan transporter Slc6a18 (XT2) is highly expressed at the luminal membrane of kidney proximal tubules and displays approximately 50% identity with Slc6a19 (B(0)AT1), which is the main neutral amino acid transporter in both kidney and small intestine. As yet, the amino acid transport function of XT2 has only been experimentally supported by the urinary glycine loss observed in xt2 null mice. We report here that in Xenopus laevis oocytes, co-expressed ACE2 (angiotensin-converting enzyme 2) associates with XT2 and reveals its function as a Na(+)- and Cl(-)-de pend ent neutral amino acid transporter. In contrast to its association with ACE2 observed in Xenopus laevis oocytes, our experiments with ace2 and collectrin null mice demonstrate that in vivo it is Collectrin, a smaller homologue of ACE2, that is required for functional expression of XT2 in kidney. To assess the function of XT2 in vivo, we reanalyzed its knock-out mouse model after more than 10 generations of backcrossing into C57BL/6 background. In addition to the previously published glycinuria, we observed a urinary loss of several other amino acids, in particular beta-branched and small neutral ones. Using telemetry, we confirmed the previously described link of XT2 absence with hypertension but only in physically restrained animals. Taken together, our data indicate that the formerly orphan transporter XT2 functions as a sodium and chloride-de pend ent neutral amino acid transporter that we propose to rename B(0)AT3.
Singer
Dustin
D
Institute of Physiology and Center for Integrative Human Physiology, University of Zürich, 8057 Zürich, Switzerland.
Camargo
Simone M R
SM
Huggel
Katja
K
Romeo
Elisa
E
Danilczyk
Ursula
U
Kuba
Keiji
K
Chesnov
Serge
S
Caron
Marc G
MG
Penninger
Josef M
JM
Verrey
Francois
F
D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism / Q000652:urine; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001692:Biological Transport; D001794:Blood Pressure; D015870:Gene Expression; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D012119:Respiration; D013379:Substrate Specificity; D014982:Xenopus laevis / Q000235:genetics
D026921:Amino Acid Transport Systems, Neutral; D000596:Amino Acids; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C504407:Tmem27 protein, mouse; C118018:Xtrp2 protein, mouse; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2