The Na(+)-K(+)-ATPase, or sodium pump, is the membrane-bound enzyme that maintains the Na(+) and K(+) gradients across the plasma membrane of animal cells. Because of its importance in many basic and specialized cellular functions, this enzyme must be able to adapt to changing cellular and physiological stimuli. This review presents an overview of the many mechanisms in place to regulate sodium pump activity in a tissue-specific manner. These mechanisms include regulation by substrates, membrane-associated components such as cytoskeletal elements and the gamma-subunit, and circulating endogenous inhibitors as well as a variety of hormones, including corticosteroids, peptide hormones, and catecholamines. In addition, the review considers the effects of a range of specific intracellular signaling pathways involved in the regulation of pump activity and subcellular distribution, with particular consideration given to the effects of protein kinases and phosphatases.

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Since the initial report of the novel Coronavirus Disease 2019 (COVID-19) emanating from Wuhan, China, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally. While the effects of SARS-CoV-2 infection are not completely understood, there appears to be a wide spectrum of disease ranging from mild symptoms to severe respiratory distress, hospitalization, and mortality. There are no Food and Drug Administration (FDA)-approved treatments for COVID-19 aside from remdesivir; early efforts to identify efficacious therapeutics for COVID-19 have mainly focused on drug repurposing screens to identify compounds with antiviral activity against SARS-CoV-2 in cellular infection systems. These screens have yielded intriguing hits, but the use of nonhuman immortalized cell lines derived from non-pulmonary or gastrointestinal origins poses any number of questions in predicting the physiological and pathological relevance of these potential interventions. While our knowledge of this novel virus continues to evolve, our current understanding of the key molecular and cellular interactions involved in SARS-CoV-2 infection is discussed in order to provide a framework for developing the most appropriate in vitro toolbox to support current and future drug discovery efforts.

The Na,K-ATPase comprises a catalytic ␣ subunit and a glycosylated ␤ subunit. Another membrane polypeptide, ␥, first described by Forbush et al. (Forbush, B., III, Kaplan, J. H., and Hoffman, J. F. (1978) Biochemistry 17, 3667-3676) associates with ␣ and ␤ in purified kidney enzyme preparations. In this study, we have used a polyclonal anti-␥ antiserum to define the tissue specificity and topology of ␥ and to address the question of whether ␥ has a functional role. The trypsin sensitivity of the amino terminus of the ␥ subunit in intact right-side-out pig kidney microsomes has confirmed that it is a type I membrane protein with an extracellular amino terminus. Western blot analysis shows that ␥ subunit protein is present only in membranes from kidney tubules (rat, dog, pig) and not those from axolemma, heart, red blood cells, kidney glomeruli, cultured glomerular cells, ␣ 1 -transfected HeLa cells, all derived from the same (rat) species, nor from three cultured cell lines derived from tubules of the kidney, namely NRK-52E (rat), LLC-PK (pig), or MDCK (dog). To gain insight into ␥ function, the effects of the anti-␥ serum on the kinetic behavior of rat kidney sodium pumps was examined. The following evidence suggests that ␥ stabilizes E 1 conformation(s) of the enzyme and that anti-␥ counteracts this effect: (i) anti-␥ inhibits Na,K-ATPase, and the inhibition increases at acidic pH under which condition the E 2 (K) 3 E 1 phase of the reaction sequence becomes more ratelimiting, (ii) the oligomycin-stimulated increase in the level of phosphoenzyme was greater in the presence of anti-␥ indicating that the antibody shifts the E 1 7 7 E 2 P equilibria toward E 2 P, and (iii) when the Na ؉ -ATPase reaction is assayed with the Na ؉ concentration reduced to levels (<2 mM) which limit the rate of the E 1 3 3 E 2 P transition, anti-␥ is stimulatory. These observations taken together with evidence that the pig ␥ subunit, which migrates as a doublet on polyacrylamide gels, is sensitive to digestion by trypsin, and that Rb ؉ ions partially protect it against this effect, indicate that the ␥ subunit is a tissue-specific regulator which shifts the steady-state equilibria toward E 1 . Accordingly, binding of anti-␥ disrupts ␣␤-␥ interactions and counteracts these modulatory effects of the ␥ subunit.

The functional role of the ␥ subunit of the Na,KATPase was studied using rat ␥ cDNA-transfected HEK-293 cells and an antiserum (␥C33) specific for ␥. Although the sequence for ␥ was verified and shown to be larger (7237 Da) Overall, our data demonstrate that ␥ is a tissue (kidney)-specific regulator of the Na,K-ATPase that can increase the apparent affinity of the enzyme for ATP in a manner that is reversible by anti-␥ antiserum.The Na,K-ATPase is the sodium pump protein responsible for maintaining the electrochemical gradient present across the membranes of most animal cells (1). It consists of at least two subunits, ␣ and ␤, each of which exists as one of several isoforms