Am J Physiol Renal Physiol 2010 Jun 01;2986:F1445-56. doi: 10.1152/ajprenal.00257.2009.

COMMD1 downregulates the epithelial sodium channel through Nedd4-2.

???displayArticle.abstract???
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.

???displayArticle.pubmedLink??? 20237237
???displayArticle.link??? Am J Physiol Renal Physiol


Species referenced: Xenopus laevis
Genes referenced: akt1 commd1 ins nedd4 nedd4l sgk1