Insulin regulates alveolar epithelial function by inducing Na+/K+-ATPase translocation to the plasma membrane in a process mediated by the action of Akt

Abstract

Stimulation of Na+/K+-ATPase translocation to the cell surface increases active Na+ transport, which is the driving force of alveolar fluid reabsorption, a process necessary to keep the lungs free of edema and to allow normal gas exchange. Here, we provide evidence that insulin increases alveolar fluid reabsorption and Na+/K+-ATPase activity by increasing its translocation to the plasma membrane in alveolar epithelial cells. Insulin-induced Akt activation is necessary and sufficient to promote Na+/K+-ATPase translocation to the plasma membrane. Phosphorylation of AS160 by Akt is also required in this process, whereas inactivation of the Rab GTPase-activating protein domain of AS160 promotes partial Na+/K+-ATPase translocation in the absence of insulin. We found that Rab10 functions as a downstream target of AS160 in insulin-induced Na+/K+-ATPase translocation. Collectively, these results suggest that Akt plays a major role in Na+/K+-ATPase intracellular translocation and thus in alveolar fluid reabsorption.

ZNRF2 is released from membranes by growth factors and, together with ZNRF1, regulates the Na+/K+ATPase

“…Examples include insulin-stimulated transport of GLUT4 glucose transporter-carrying vesicles to the plasma membrane to allow glucose to enter muscles and adipose tissues (Rowland et al, 2011;Taniguchi et al, 2006), increased cell surface expression of the Na + /K + ATPase to clear postprandial blood K + (Al-Khalili et al, 2003;Comellas et al, 2010) and membrane dynamics associated with inhibiting apoptosis and autophagy (Eisenberg-Lerner et al, 2009). However, too few downstream components have been defined to fully explain how the PI3K-PKB pathway regulates such membrane events, and ZNRF1 and ZNRF2 seemed attractive candidate mediators.…”

“…The pump is also regulated acutely; for example the skeletal muscle Na + /K + ATPase activity is enhanced by insulin to clear blood K + after a meal, and by adrenaline and contraction to prevent fatigue (Ewart and Klip, 1995;Hatou et al, 2010). Demands for the Na + / K + ATPase also change markedly during nerve excitation, renal blood filtration and breathing, and Na + /K + ATPases are highly regulated in context-dependent ways by adrenaline, dopamine, thyroid hormone, aldosterone, catecholamines and insulin (reviewed by Comellas et al, 2010;Ewart and Klip, 1995). Mechanistic details of these regulations are sketchy, though protein kinases including PKA, PKC and SGK have been found to phosphorylate the a and FXYD subunits, triggering trafficking of the Na + /K + ATPase between intercellular membranes and cell surface, as well as changing intrinsic activity of the pump (Fuller et al, 2009;Han et al, 2010;Lang et al, 2010;Poulsen et al, 2010).…”

Resolvin D1 Stimulates Alveolar Fluid Clearance through Alveolar Epithelial Sodium Channel, Na,K-ATPase via ALX/cAMP/PI3K Pathway in Lipopolysaccharide-Induced Acute Lung Injury

“…Na,KATPase is composed of an a subunit that hydrolyzes ATP and exchanges intracellular Na + for extracellular K + , and a b subunit that controls enzyme assembly and insertion into the plasma membrane (15,50). Early studies showed AFC was increased by upregulation of Na,K-ATPase activity and facilitates the expression of Na,K-ATPase in alveolar cells (10,51). Analogously, our study demonstrates that RvD1 not only increases Na,K-ATPase a1 expression in rat lung tissues and primary ATII cells after LPS challenge by Western blotting, immunohistochemistry, and confocal laser-scanning microscopy measurement, but also upregulation of Na,K-ATPase activity in vivo and in vitro.…”

Akt Substrate of 160 kD Regulates Na+,K+-ATPase Trafficking in Response to Energy Depletion and Renal Ischemia

“…11,13,41 Recently, Comellas et al suggested that Rab 10 is implicated in sodium pump trafficking in response to insulin in pulmonary cells. 42 It will be important to identify the Rab protein involved in the AS160-mediated Na,K-ATPase trafficking in response to energy depletion, as well as the role of the GAP domain of AS160 in this process.…”