ResearchIn-Press PreviewCell biologyNephrology
Open Access | 10.1172/jci.insight.172051
1Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America
2Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America
3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
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1Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America
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3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
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1Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America
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1Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America
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1Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America
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1Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America
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1Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America
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3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
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1Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America
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1Department of Medicine, University of Pittsburgh, Pittsburgh, United States of America
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3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
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Published September 14, 2023 - More info
Epithelial Na+ channels (ENaCs) control extracellular fluid volume by facilitating Na+ absorption across transporting epithelia. In vitro studies showed that Cys-palmitoylation of the γ ENaC subunit is a major regulator of channel activity. We tested whether γ subunit palmitoylation sites are necessary for channel function in vivo by generating mice lacking the palmitoylated cysteines (γC33A,C41A) using CRISPR-Cas9 technology. ENaCs in dissected kidney tubules from γC33A,C41A mice had reduced open probability compared to wild type (WT) littermates maintained on either standard or Na+-deficient diets. Male mutant mice also had higher aldosterone levels than WT littermates following Na+ restriction. However, γC33A,C41A mice did not have reduced amiloride-sensitive Na+ currents in the distal colon or benzamil-induced natriuresis compared to WT mice. We identified a second, larger conductance cation channel in the distal nephron with biophysical properties distinct from ENaC. The activity of this channel was higher in Na+-restricted γC33A,C41A versus WT mice and was blocked by benzamil, providing a possible compensatory mechanism for reduced prototypic ENaC function. We conclude that γ subunit palmitoylation sites are required for prototypic ENaC activity in vivo, but are not necessary for amiloride/benzamil-sensitive Na+ transport in the distal nephron or colon.