FXYD Proteins: New Tissue-Specific Regulators of the Ubiquitous Na,K-ATPase

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Science's STKE  21 Jan 2003:
Vol. 2003, Issue 166, pp. re1
DOI: 10.1126/stke.2003.166.re1

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The Na,K-ATPase is a plasma membrane enzyme that is responsible for maintaining the Na+ and K+ gradients between the intra- and extracellular milieu of animal cells. It consists of a catalytic α subunit and a regulatory β subunit. Na,K-ATPase transports Na+ out of the cell and K+ into the cell against their respective chemical gradients by using energy derived from the hydrolysis of ATP. Maintenance of the Na+ and K+ gradients by the Na,K-ATPase is essential for basic cellular homeostasis as well as for specialized functions of various tissues. Rigorous control of the Na+ and K+ gradients by Na,K-ATPase is necessary for preservation of cell volume, maintenance of membrane potential, and activity of secondary transporters that provide the cell with nutrients or regulate cellular solute concentrations. Moreover, in renal epithelial cells, the Na,K-ATPase, exclusively located in the basolateral membrane, is the driving force for the Na+ reabsorption that maintains extracellular volume and, hence, blood pressure. In addition, in heart and skeletal muscle, the activity of Na,K-ATPase is tightly coupled to the activity of a Na+/Ca2+-exchanger that controls muscle contraction. Finally, in the nervous system, Na,K-ATPase contributes to the re-establishment of the basal Na+ and K+ gradients both during action potentials and consequent to neuronal excitation. The Na,K-ATPase must be finely regulated to fulfil its important tasks under changing physiological conditions. Tissue-specific differences in Na,K-ATPase activity are achieved by the expression of four α and three β isoforms, which potentially can form 12 Na,K-ATPase isozymes with different functional properties. Moreover, various hormones and neurotransmitters are involved in the short- and long-term control of Na,K-ATPase; they regulate its activity and/or expression through protein kinase phosphorylation or transcriptional control. In this review, we discuss a novel regulatory mechanism of Na,K-ATPase that is mediated by the interaction of Na,K-ATPase with small membrane proteins of the FXYD family that so far have been considered as channels or regulators of ion channels. The FXYD proteins FXYD1 through FXYD7 exhibit tissue-specific distribution. FXYD1 (phospholemman) in heart and skeletal muscle, FXYD2 (the γ subunit of Na,K-ATPase) and FXYD4 [corticosteroid hormone-induced factor (CHIF)] in the kidney, and FXYD7 in the brain associate preferentially with the Na,K-ATPase α1-β1 isozyme and modulate its transport properties in a way that conforms to tissue-specific requirements. Thus, FXYD proteins contribute to proper handling of Na+ and K+ by the most widely expressed Na,K-ATPase α1-β1 isozymes, and ensure correct function in such mechanisms as renal Na+ reabsorption, muscle contraction, and neuronal excitability