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COMMD1 downregulates the epithelial sodium channel through Nedd4-2.
Am J Physiol Renal Physiol. 2010 Jun; 298(6):F1445-56.AJ

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.

Authors+Show Affiliations

Department of Physiology, University of Otago, Dunedin, New Zealand.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20237237

Citation

Ke, Ying, et al. "COMMD1 Downregulates the Epithelial Sodium Channel Through Nedd4-2." American Journal of Physiology. Renal Physiology, vol. 298, no. 6, 2010, pp. F1445-56.
Ke Y, Butt AG, Swart M, et al. COMMD1 downregulates the epithelial sodium channel through Nedd4-2. Am J Physiol Renal Physiol. 2010;298(6):F1445-56.
Ke, Y., Butt, A. G., Swart, M., Liu, Y. F., & McDonald, F. J. (2010). COMMD1 downregulates the epithelial sodium channel through Nedd4-2. American Journal of Physiology. Renal Physiology, 298(6), F1445-56. https://doi.org/10.1152/ajprenal.00257.2009
Ke Y, et al. COMMD1 Downregulates the Epithelial Sodium Channel Through Nedd4-2. Am J Physiol Renal Physiol. 2010;298(6):F1445-56. PubMed PMID: 20237237.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - COMMD1 downregulates the epithelial sodium channel through Nedd4-2. AU - Ke,Ying, AU - Butt,A Grant, AU - Swart,Marianne, AU - Liu,Yong Feng, AU - McDonald,Fiona J, Y1 - 2010/03/17/ PY - 2010/3/19/entrez PY - 2010/3/20/pubmed PY - 2010/6/15/medline SP - F1445 EP - 56 JF - American journal of physiology. Renal physiology JO - Am J Physiol Renal Physiol VL - 298 IS - 6 N2 - 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. SN - 1522-1466 UR - https://www.unboundmedicine.com/medline/citation/20237237/COMMD1_downregulates_the_epithelial_sodium_channel_through_Nedd4_2_ L2 - https://journals.physiology.org/doi/10.1152/ajprenal.00257.2009?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -