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1 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
2 Department of Pharmacology, New York Medical College, Valhalla, NY, USA
* To whom correspondence should be addressed. E-mail: steven.hebert{at}yale.edu.
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 (15). However, a distinct 70pS 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 (NPo = 0.02) in ROMK(+/+) mice on a control K diet, but increased to 0.27 by high K intake for 2 weeks. In contrast, the high K diet decreased NPo of SK by ~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 (+/+) mice (0.95 vs. 2.04). The high K diet also reduced SK activity in ROMK(+/-) mice by ~40% (from 0.95 to 0.55) but increased NPo of the 70 pS K channel from 0 to 0.09 in (+/-) mice. This corresponds to ~30% of channel activity (NPo = 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.
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