COMMD1 downregulates the epithelial sodium channel through Nedd4-2.
The epithelial sodium channel (ENaC) is important for the long-term control of Na(+) homeostasis and blood pressure. Our previous studies demonstrated that Copper Metabolism Murr1 Domain-containing protein 1 (COMMD1; previously known as Murr1), a protein involved in copper metabolism, inhibited amiloride-sensitive current in Xenopus laevis oocytes expressing ENaC (J Biol ... Chem 279: 5429, 2004). In this study, we report that COMMD1 inhibits amiloride-sensitive current in mammalian epithelial cells expressing ENaC, that the COMM domain of COMMD1 is sufficient for this effect, and that knockdown of COMMD1 increases amiloride-sensitive current. COMMD1 is coexpressed with ENaC in rat kidney medulla cells. COMMD1 increased ubiquitin modification of ENaC and decreased its cell surface expression. COMMD1 abolished insulin-stimulated amiloride-sensitive current and attenuated the stimulation of current by activated serum and glucocorticoid-regulated kinase (SGK1). COMMD1 was found to interact with both SGK1 and Akt1/protein kinase B, and knockdown of COMMD1 enhanced the stimulatory effect of both SGK1 and Akt1 on amiloride-sensitive current. COMMD1's effects were reduced in the presence of ENaC proteins containing PY motif mutations, abolished in the presence of a dominant negative form of Nedd4-2, and knockdown of COMMD1 reduced the inhibitory effect of Nedd4-2 on ENaC, but did not enhance current when Nedd4-2 was knocked down. These data suggest that COMMD1 modulates Na(+) transport in epithelial cells through regulation of ENaC cell surface expression and this effect is likely mediated via Nedd4-2.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amiloride, Animals, COS Cells, Carrier Proteins, Cercopithecus aethiops, Down-Regulation, Endosomal Sorting Complexes Required for Transport, Epithelial Cells, Epithelial Sodium Channel, Female, Humans, Immediate-Early Proteins, Insulin, Kidney Medulla, Membrane Potentials, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, RNA Interference, Rats, Rats, Inbred F344, Rats, Wistar, Recombinant Fusion Proteins, Sodium, Sodium Channel Blockers, Thyroid Gland, Transfection, Ubiquitin-Protein Ligases, Ubiquitination
Adaptor Proteins, Signal Transducing, Amiloride, Animals, COS Cells, Carrier Proteins, Cercopithecus aethiops, Down-Regulation, Endosomal Sorting Complexes Required for Transport, Epithelial Cells, Epithelial Sodium Channel, Female, Humans, Immediate-Early Proteins, Insulin, Kidney Medulla, Membrane Potentials, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, RNA Interference, Rats, Rats, Inbred F344, Rats, Wistar, Recombinant Fusion Proteins, Sodium, Sodium Channel Blockers, Thyroid Gland, Transfection, Ubiquitin-Protein Ligases, Ubiquitination
Am. J. Physiol. Renal Physiol.
Date: Jun. 01, 2010
PubMed ID: 20237237
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