The Na⁺-K⁺-ATPase as self-adhesion molecule and hormone receptor

Abstract

Thanks to the homeostasis of the internal milieu, metazoan cells can enormously simplify their housekeeping efforts and engage instead in differentiation and multiple forms of organization (tissues, organs, systems) that enable them to produce an astonishing diversity of mammals. The stability of the internal milieu despite drastic variations of the external environment (air, fresh or seawater, gastrointestinal fluids, glomerular filtrate, bile) is due to transporting epithelia that can adjust their specific permeability to H(2)O, H(+), Na(+), K(+), Ca(2+), and Cl(-) over several orders of magnitude and exchange substances with the outer milieu with exquisite precision. This exchange is due to the polarized expression of membrane proteins, among them Na(+)-K(+)-ATPase, an oligomeric enzyme that uses chemical energy from ATP molecules to translocate ions across the plasma membrane of epithelial cells. Na(+)-K(+)-ATPase presents two types of asymmetries: the arrangement of its subunits, and its expression in one pole of the epithelial cell ("polarity"). In most epithelia, polarity consists of the expression of Na(+)-K(+)-ATPase towards the intercellular space and arises in part from the interaction of the extracellular segment of the β-subunit with another β-subunit present in a Na(+)-K(+)-ATPase molecule expressed by a neighboring cell. In addition to enabling the Na(+)-K(+)-ATPase to transport ions and water vectorially, this position exposes its receptors to ouabain and analogous cardiotonic steroids, which are present in the internal milieu because these were secreted by endocrine cells.

Ouabain Increases Gap Junctional Communication in Epithelial Cells

“…In summary, the two experimental approaches concur in demonstrating that 10 nM ouabain enhances GJC. Taken together, these observations strengthen our general hypothesis that ouabain modulates cell contacts [9]; as it is also in keeping with our previous observations of TJ [14] and ciliogenesis [15]. …”

“…The plasma levels of ouabain increase in response to muscular exercise, a high-sodium diet and pathological conditions, such as eclampsia, certain forms of arterial hypertension and myocardial infarction [2,3,4,5,6,7]. The available experimental evidence suggests that the endogenous cardiac steroids are hormones [8,9,10], raising the question of their physiological role.…”

“…Therefore, we hypothesized that one physiological role of ouabain is the modulation of cell contacts [9,13]. We have already shown that low, non-toxic concentrations of ouabain modulate the hermeticity and molecular composition of tight junctions (TJ) [14].…”

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

“…In contrast to FXYD5, the Na,K-ATPase α-β heterodimer contributes to the formation and stabilization of intercellular junctions in epithelia (Cereijido et al, 2012;Rajasekaran and Rajasekaran, 2009;Vagin et al, 2012). It acts as a cell adhesion molecule by undergoing both intercellular trans-dimerization through its β 1 subunit and intracellular association with the cytoskeleton through its α 1 subunit (Clifford and Kaplan, 2008;Shoshani et al, 2005).…”

Subunit Isoform Selectivity in Assembly of Na,K-ATPase α-β Heterodimers

“…The ␣ 4 isoform is required for sperm motility and fertility (10,11). The ␤ 1 subunit plays an important role in intercellular adhesion in epithelia (17,18), and the ␤ 2 subunit, or adhesion molecule on glia (AMOG), 2 is important for adhesion and migration of neurons on glia (19). Decreased expression of the ␤ 1 subunit is associated with cancer (reviewed in Ref.…”