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The Na,K-ATPase, consisting of a catalytic α-subunit and a regulatory β-subunit, is a ubiquitously expressed ion pump that carries out the transport of Na+ and K+ across the plasma membranes of most animal cells. In addition to its pump function, Na,K-ATPase serves as a signaling scaffold and a cell adhesion molecule. Of the three β-subunit isoforms, β1 is found in almost all tissues, while β2 expression is mostly restricted to brain and muscle. In cerebellar granule cells, the β2-subunit, also known as adhesion molecule on glia (AMOG), has been linked to neuron-astrocyte adhesion and granule cell migration, suggesting its role in cerebellar development. Nevertheless, little is known about molecular pathways that link the β2-subunit to its cellular functions. Using cerebellar granule precursor cells, we found that the β2-subunit, but not the β1-subunit, negatively regulates the expression of a key activator of the Hippo/YAP signaling pathway, Merlin/neurofibromin-2 (NF2). The knockdown of the β2-subunit resulted in increased Merlin/NF2 expression and affected downstream targets of Hippo signaling, i.e., increased YAP phosphorylation and decreased expression of N-Ras. Further, the β2-subunit knockdown altered the kinetics of epidermal growth factor receptor (EGFR) signaling in a Merlin-dependent mode and impaired EGF-induced reorganization of the actin cytoskeleton. Therefore, our studies for the first time provide a functional link between the Na,K-ATPase β2-subunit and Merlin/NF2 and suggest a role for the β2-subunit in regulating cytoskeletal dynamics and Hippo/YAP signaling during neuronal differentiation.

The gastric H,K-ATPase, a member of the P(2)-type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an alpha,beta-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic alpha subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8. Comparison to the known structure of the SERCA pump, mutagenesis, and molecular modeling has identified these as constituents of the ion binding domain. The beta subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the beta subunit contains six or seven N-linked glycosylation sites. N-glycosylation is important for the enzyme assembly, maturation, and sorting. The enzyme pumps acid by a series of conformational changes from an E(1) (ion site in) to an E(2) (ion site out) configuration following binding of MgATP and phosphorylation. Several experimental observations support the hypothesis that expulsion of the proton at 160 mM (pH 0.8) results from movement of lysine 791 into the ion binding site in the E(2)P configuration. Potassium access from the lumen depends on activation of a K and Cl conductance via a KCNQ1/KCNE2 complex and Clic6. K movement through the luminal channel in E(2)P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E(1) configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases.

Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists.

The Na,K-ATPases and the H,K-ATPases are two potassium-dependent homologous heterodimeric P2-type pumps that catalyze active transport of Na+ in exchange for K+ (Na,K-ATPase) or H+ in exchange for K+ (H,K-ATPase). The ubiquitous Na,K-ATPase maintains intracellular ion balance and membrane potential. The gastric H,K-ATPase is responsible for acid secretion by the parietal cell of the stomach. Both pumps consist of a catalytic α-subunit and a glycosylated β-subunit that is obligatory for normal pump maturation and trafficking. Individual N-glycans linked to the β-subunits of the Na,K-ATPase and H,K-ATPase are important for stable membrane integration of their respective α subunits, folding, stability, subunit assembly, and enzymatic activity of the pumps. They are also essential for the quality control of unassembled β-subunits that results in either the exit of the subunits from the ER or their ER retention and subsequent degradation. Overall, the importance of N-glycans for the␣maturation and quality control of the H,K-ATPase is greater than that of the Na,K-ATPase. The roles of individual N-glycans of the β-subunits in the post-ER trafficking, membrane targeting and plasma membrane retention of the Na,K-ATPase and H,K-ATPase are different. The Na,K-ATPase β 1-subunit is the major β-subunit isoform in cells with lateral location of the pump. All three N-glycans of the Na,K-ATPase β 1-subunit are important for the lateral membrane retention of the pump due to glycan-mediated interaction between the β 1-subunits of the two neighboring cells in the cell monolayer and cytosolic linkage of the α-subunit to the cytoskeleton. This intercellular β 1–β 1 interaction is also important for formation of cell–cell contacts. In contrast, the N-glycans unique to the Na,K-ATPase β 2-subunit,which has up to eight N-glycosylation sites, contain apical sorting information. This is consistent with the apical location of the Na,K-ATPase in normal and malignant epithelial cells with high abundance of the β 2-subunit. Similarly, all seven N-glycans of the gastric H,K-ATPase β-subunit determine apical sorting of this subunit.