The expression and activity of many membrane transport proteins are inhibited under conditions of metabolic stress, thereby limiting the dissipation of ionic gradients and preserving the energy required to maintain them. However, the mechanisms involved in this inhibition are unclear. We have established the AMP-activated kinase (AMPK), a metabolic sensor and key regulator of cellular energy homeostasis, as an important potential link between cellular metabolism and ion transport activity. We recently found that AMPK inhibits the epithelial Na+ channel (ENaC), the rate-limiting pathway for renal salt reabsorption and a major regulator of total body volume status and blood pressure, by decreasing channel expression at the plasma membrane. However, AMPK does not bind or phosphorylate ENaC In vitro, suggesting that AMPK inhibits ENaC indirectly through other signaling pathways. Several lines of evidence suggest that Nedd4-2, a ubiquitin-protein ligase that promotes ENaC internalization and degradation, plays a central role in the regulation of ENaC by AMPK. AMPK-dependent ENaC inhibition is prevented in oocytes expressing an ENaC mutant that does not bind Nedd4-2, or in oocytes co-expressing ENaC and dominant-negative or constitutively active Nedd4-2 mutants. Moreover, AMPK phosphorylates Nedd4-2, suggesting a possible mechanism for AMPK-dependent modulation of Nedd4-2 and thus ENaC activity. Our central hypothesis is that AMPK plays a crucial role in the coupling of epithelial transport to cellular metabolic status through its regulation of important transport proteins such as ENaC. We further propose that ENaC inhibition by AMPK occurs via AMPK phosphorylation-dependent modulation of Nedd4-2 function.
The specific aims of this project are to: (1) determine the mechanism of AMPK-dependent inhibition of ENaC expression at the plasma membrane by measuring ENaC half-life, endocytosis and delivery rates at the plasma membrane as a function of AMPK activation;(2) examine the role of AMPK-dependent Nedd4-2 phosphorylation in the regulation of ENaC;and (3) determine the role of AMPK in the inhibition of ENaC in response to chemically induced metabolic stress. Results obtained from these studies should provide specific mechanistic insights into how ENaC is regulated by AMPK and broader insights into the coupling of ion transport to cellular metabolism. They should also promote our understanding of the consequences and pathogenic details of ischemic tissue injury, and the pathophysiology of common diseases, such as hypertension and cystic fibrosis, which are all relevant public health concerns.
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