AMP‐activated Kinase Inhibits KCNQ1 Channels through Regulation of the Ubiquitin Ligase Nedd4‐2

Abstract

The KCNQ1 K+ channel ia a regulator of body electrolyte homeostasis. The metabolic sensor AMP‐activated kinase (AMPK) regulates several ion transporters. To determine whether AMPK regulates KCNQ1, we studied the effects of AMPK activation on KCNQ1 currents in Xenopus oocytes. AMPK activation decreased KCNQ1 currents, but AMPK did not phosphorylate KCNQ1 in vitro, suggesting an indirect regulatory mechanism. Recently, it has been shown that Nedd4‐2 inhibits KCNQ1 by decreasing plasma membrane expression. Previous studies from our group have shown that AMPK down‐regulates epithelial Na+ channels via regulation of Nedd4‐2. Therefore, we examined the role of Nedd4‐2 in the AMPK‐dependent regulation of KCNQ1. Channel inhibition by AMPK was blocked in oocytes coexpressing either a dominant‐negative or constitutively active Nedd4‐2 mutant, or a KCNQ1 PY motif mutant, suggesting that AMPK‐dependent modulation of Nedd4‐2 is involved in the regulation. In kidney slices the AMPK activator AICAR induced intracellular redistribution of KCNQ1 from the plasma membrane in the collecting duct. These results suggest that AMPK inhibits KCNQ1 activity by promoting Nedd4‐2‐dependent channel retrieval from the plasma membrane. KCNQ1 inhibition by AMPK may limit cellular K+ recycling under conditions of metabolic stress, thus reducing cellular energy expenditure for ion transport in epithelia. (Funded by NIH and AHA)