MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2.
The renal proximal tubule reabsorbs 90% of the filtered glucose load through the Na+-coupled glucose transporter SGLT2, and specific inhibitors of SGLT2 are now available to patients with diabetes to increase urinary glucose excretion. Using expression cloning, we identified an accessory protein, 17 kDa membrane-associated protein (MAP17), that increased SGLT2 activity in RNA-injected Xenopus oocytes by two orders of magnitude. Significant stimulation of SGLT2 activity also occurred in opossum kidney cells cotransfected with SGLT2 and MAP17. Notably, transfection with MAP17 did not change the quantity of SGLT2 protein at the cell surface in either cell type. To confirm the physiologic relevance of the MAP17-SGLT2 interaction, we studied a cohort of 60 individuals with familial renal glucosuria. One patient without any identifiable mutation in the SGLT2 coding gene (SLC5A2) displayed homozygosity for a splicing mutation (c.176+1G>A) in the MAP17 coding gene (PDZK1IP1). In the proximal tubule and in other tissues, MAP17 is known to interact with PDZK1, a scaffolding protein linked to other transporters, including Na+/H+exchanger 3, and to signaling pathways, such as the A-kinase anchor protein 2/protein kinase A pathway. Thus, these results provide the basis for a more thorough characterization of SGLT2 which would include the possible effects of its inhibition on colocalized renal transporters.
Physics Department & Groupe d'étude des protéines membranaires.
Michael J
MJ
Coady
Departement of Molecular and Integrative Physiology & Groupe d'étude des protéines membranaires, and.
Abdulah
A
El Tarazi
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and.
René
R
Santer
Departement of Molecular and Integrative Physiology & Groupe d'étude des protéines membranaires, and.
Pierre
P
Bissonnette
Physics Department & Groupe d'étude des protéines membranaires.
Louis J
LJ
Sasseville
Department of Nephrology, ToxOmics, Centre for Toxicogenomics and Human Health, NOVA Medical School, New University of Lisbon, Lisbon, Portugal.
Joaquim
J
Calado
Departement of Molecular and Integrative Physiology & Groupe d'étude des protéines membranaires, and.
Yoann
Y
Lussier
Departement of Molecular and Integrative Physiology & Groupe d'étude des protéines membranaires, and.
Christopher
C
Dumayne
Departement of Molecular and Integrative Physiology & Groupe d'étude des protéines membranaires, and.|Department of Medicine, Centre de recherche de l'Hôpital du Sacré-Cœur, University of Montreal, Montreal, Quebec, Canada.
Daniel G
DG
Bichet
Physics Department & Groupe d'étude des protéines membranaires, jean-yves.lapointe@umontreal.ca.
Jean-Yves
JY
Lapointe
D000818:Animals; D002478:Cells, Cultured; D006030:Glycosuria, Renal / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D007687:Kidney Tubules, Proximal; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009893:Opossums; D051297:Sodium-Glucose Transporter 2 / Q000502:physiology*
D008565:Membrane Proteins; C509768:PDZK1IP1 protein, human; D051297:Sodium-Glucose Transporter 2
Na transport; cell & transport physiology; diabetes; glucose reabsorption; ion transport