A tyrosine-based signal regulates H-K-ATPase-mediated potassium reabsorption in the kidney.
Isoforms of the H-K-ATPase participate in active K resorption in the renal collecting tubule. The cytoplasmic tail of the beta-subunit of the gastric H-K-ATPase includes a 4 amino acid motif which is highly homologous to tyrosine-based endocytosis signals. We have generated transgenic mice expressing an H-K-ATPase beta-subunit in which the tyrosine residue in this sequence has been mutated to alanine. Mice expressing the mutated protein manifest constitutive hypersecretion of gastric acid, demonstrating that the beta-subunit tyrosine-based motif is required for the regulated endocytosis of the H-K pump and hence the cessation of gastric acid output. To test the possibility that the tyrosine-based sequence in the tail of the H-K-ATPase beta-subunit plays a role in regulating the function of renal H-K-ATPases, we examined renal K clearance in normal and in transgenic mice. Blood pressure, urine volume, glomerular filtration rate (GFR), plasma Na, and Na excretion are similar in control and transgenic mice. However, plasma K concentrations are significantly higher in transgenic mice (4.76 +/- 0.13 meq/l in transgenic and 4. 12 +/- 0.04 meq/l in control; n = 9, P < 0.05) and K excretion is lower in the transgenic animals (fractional excretion of K was 26.2 +/- 3.62% in transgenic and 50.1 +/- 4.78% in control; n = 9, P < 0. 01). These data suggest that the tyrosine-based signal in the cytoplasmic tail of the H-K-ATPase beta-subunit functions in the kidney as it does in the stomach to internalize H-K pump and thus inactivate pump function. Its elimination may result in the constitutive presence of the pump at the cell surface and lead to excessive urinary K reabsorption.
Wang
T
T
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Courtois-Coutry
N
N
Giebisch
G
G
Caplan
M J
MJ
D000818:Animals; D017506:H(+)-K(+)-Exchanging ATPase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011188:Potassium / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D014443:Tyrosine; D017506:H(+)-K(+)-Exchanging ATPase; D011188:Potassium