Regulation of the voltage-gated K⁺ channels KCNQ2/3 and KCNQ3/5 by serum- and glucocorticoid-regulated kinase-1

Abstract

The voltage-gated KCNQ2/3 and KCNQ3/5 K(+) channels regulate neuronal excitability. We recently showed that KCNQ2/3 and KCNQ3/5 channels are regulated by the ubiquitin ligase Nedd4-2. Serum- and glucocorticoid-regulated kinase-1 (SGK-1) plays an important role in regulation of epithelial ion transport. SGK-1 phosphorylation of Nedd4-2 decreases the ability of Nedd4-2 to ubiquitinate the epithelial Na(+) channel, which increases the abundance of channel protein in the cell membrane. In this study, we investigated the mechanism(s) of SGK-1 regulation of M-type KCNQ channels expressed in Xenopus oocytes. SGK-1 significantly upregulated the K(+) current amplitudes of KCNQ2/3 and KCNQ3/5 channels approximately 1.4- and approximately 1.7-fold, respectively, whereas the kinase-inactive SGK-1 mutant had no effect. The cell surface levels of KCNQ2-hemagglutinin/3 were also increased by SGK-1. Deletion of the KCNQ3 channel COOH terminus in the presence of SGK-1 did not affect the K(+) current amplitude of KCNQ2/3/5-mediated currents. Coexpression of Nedd4-2 and SGK-1 with KCNQ2/3 or KCNQ3/5 channels did not significantly alter K(+) current amplitudes. Only the Nedd4-2 mutant (S448A)Nedd4-2 exhibited a significant downregulation of the KCNQ2/3/5 K(+) current amplitudes. Taken together, these results demonstrate a potential mechanism for regulation of KCNQ2/3 and KCNQ3/5 channels by SGK-1 regulation of the activity of the ubiquitin ligase Nedd4-2.

Mechanisms Underlying Rapid Aldosterone Effects in the Kidney

“…Modulation of NHE activity by aldosterone may also contribute to the activation of pHsensitive K + ATP channels in the basolateral membrane to promote K + recycling (113). Other mechanisms for the regulation of apical K + channel activity rely upon elevated SGK1 activity either to suppress Nedd4-2, which ubiquitinates KCNQ2-and KCNQ3-type K + channels (114,115), or to modulate ROMK activity through direct phosphorylation of WNK4 by SGK1 (14). ROMK is the principal K + -secreting channel in the kidney and is expressed apically along the ASDN (116).…”

Role of the ubiquitin system in regulating ion transport

“…These Nedd4 family members thus affect channel ubiquitylation and internalization. Likewise, the muscarinic-sensitive K + current (M-current), mediated by heterotetrameric channels consisting of KCNQ3 associated with either KCNQ2 or KCNQ5 (i.e., KCNQ2/3 or KCNQ3/5), are regulated by Nedd4-2, ubiquitylation and Sgk1 [50,175]. The C termini of KCNQ2 and KCNQ3 contain an atypical "PY motif" (PPxPPY).…”

“…Active Nedd4-2 is required to suppress function of these channels, suggesting that ubiquitylation regulates their stability, likely at the cell surface [50]. Similar to ENaC, the regulation of KCNQ2/3 and KCNQ3/ 5 via Nedd4-2 can be modulated by Sgk1 mediated phosphorylation of this E3 ligase [175].…”

Endocytic regulation of alkali metal transport proteins in mammals, yeast and plants

“…Nedd4-2 (Ekberg, et al 2007, Schuetz, et al 2008) KCNA3/KCNA5 Nedd4-2 (Boehmer, et al 2008, Henke, et al 2004) KCNJ2…”