ROMK is required for expression of the 70-pS K channel in the thick ascending limb.
Apical potassium recycling is crucial for salt transport by the thick ascending limb (TAL). Loss-of-function mutations in the K channel, ROMK (Kir1.1; KCNJ1), cause Bartter syndrome, a genetically heterogeneous disorder characterized by severe reduction in salt absorption by the TAL, Na wasting, polyuria, and hypokalemic alkalosis. ROMK(-/-) null mice exhibit a Bartter phenotype and lack the small-conductance (30-pS) apical K channel (SK) in the TAL. However, a distinct 70-pS K channel can also significantly contribute to the apical conductance of TAL. We now examine the effect of ROMK deletion on the functional expression of the 70-pS K channel in the TAL. Functional expression of the 70-pS K channel was low [average channel activity (NP(o)) = 0.02] in ROMK(+/+) mice on a control K diet but increased to 0.27 by high-K intake for 2 wk. In contrast, the high-K diet decreased NP(o) of SK by approximately 30%, from 2.04 to 1.44. In ROMK heterozygous (+/-) mice on a control K diet, SK activity was about one-half of that observed in ROMK(+/+) mice (0.95 vs. 2.04). The high-K diet also reduced SK activity in ROMK(+/-) mice by approximately 40% (from 0.95 to 0.55) but increased NP(o) of the 70-pS K channel from 0 to 0.09 in ROMK(+/-) mice. This corresponds to approximately 30% of channel activity (NP(o) = 0.27) observed in ROMK(+/+) mice. Neither the 70-pS nor the 30-pS K channels were observed in TAL cells from ROMK(-/-) mice on either the normal or high-K diets. Thus functional expression of the 70-pS K channel is enhanced by increasing dietary K and requires expression of ROMK. It is likely that ROMK forms a critical subunit of the 70-pS K channel, accounting for the loss of apical K secretory channel activity in ROMK Bartter syndrome.
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8026, USA.
Ming
M
Lu
Tong
T
Wang
Qingshang
Q
Yan
Wenhui
W
Wang
Gerhard
G
Giebisch
Steven C
SC
Hebert
D000284:Administration, Oral; D000818:Animals; D004553:Electric Conductivity; D007686:Kidney Tubules, Distal / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000008:administration & dosage / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying
C510693:Kcnj1 protein, mouse; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011188:Potassium