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Melanophilin, a novel aldosterone-induced gene in mouse cortical collecting duct cells

Dartmouth Medical School, Lebanon, New Hampshire

Submitted 11 September 2006 ; accepted in final form 28 June 2007

The molecular mechanisms of aldosterone-regulated Na⁺ transport are not entirely clear. The goal of this study was to identify aldosterone-induced genes potentially involved in the trafficking of the epithelial Na⁺ channel (ENaC). We report that the transcript levels of melanophilin (MLPH), a protein involved in vesicular trafficking in melanocytes, are rapidly increased by aldosterone in cortical collecting duct (CCD) cells. This effect was near maximal at physiological aldosterone concentrations, indicating that it is mediated by the mineralocorticoid receptor. De novo protein synthesis is not required for the induction of MLPH mRNA by aldosterone. To determine whether this induction has functional consequences on transepithelial Na⁺ current, we generated clonal CCD cell lines that express a tetracycline-inducible MLPH. Induction of MLPH in these cells led to a relatively modest, but statistically significant, increase in amiloride-sensitive Na⁺ current, suggesting the MLPH may be involved in ENaC trafficking. MyosinVc, the epithelial-specific class V myosin that is highly homologous to MyosinVa, another component of the melanosome trafficking complex, has putative consensus sites for serum and glucocorticoid-induced kinase 1 (SGK1), an early aldosterone-induced kinase that mediates some of aldosterone's effects on Na⁺ transport. Our results indicate that MyosinVc is phosphorylated by endogenous SGK1, suggesting that this complex may be involved in the aldosterone-regulated trafficking of ENaC in the CCD. These results suggest potential mechanisms by which aldosterone may regulate Na⁺ transport both directly, by increasing the abundance of MLPH, and indirectly by increasing the transcription of SGK1, which in turn regulates the activity of MyosinVc.

epithelial Na⁺ channel; myosin; serum and glucocorticoid-induced kinase