One Recently, ouabain has been found to

One proposal combinesthe relationship between Bcl-2 protein cytosolic concentrations and Bcl-2 interactionspossibly altered through their reciprocal interaction with NKA.  This interaction would occur due to BH-1 andBH-3 motifs, previously identified upon sequence analysis of crystalized NKA(Lauf et al., 2013).  These putativemotifs found on NKA could interact directly with the pro- and anti-apoptoticBcl-2 subfamilies thereby having a direct effect on cell signaling andsurvival.

  In conjunction with thistheory, a research group in Sweden showed that in rat proximal tubule cells,ouabain attenuated the imbalance between the pro-apoptotic effects of BAX and itsinhibitor Bcl-XL (Burlaka et al., 2013). We propose CTS-driven effects correspond with NKA inhibition and NKA’sBcl-2 motifs and possible unveiling of BH-3 motifs that interact within thecell.Caveolin-1Caveolae were firstidentified as flask-shaped, noncoated vesicular membrane invaginations (Liu etal., 2004).  Caveolins are 21 to 24 kDamembrane-associated scaffold proteins and the major structural components ofcaveolae (Liu et al., 2004). The principal site where one would expectcaveolin-1 to function in membrane traffic is at the caveola (Liu et al.

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, 2002).  Recently, ouabain has been found to initiate endocytosisof the NKA receptor in proximal tubule cells, but only when caveolin-1 ispresent (Liu et al., 2004).  Caveolae arewell known for their unique endocytic properties (Liu et al., 2002).

  There are three caveolin genes expressed inmammals (designated caveolin-1, -2, and -3), and they code for five differentisoforms of the protein (Liu et al., 2002). Caveolin typically functions as a scaffold for lipid transport withinthe cells interacting with cholesterol creating lipid rafts, which are transportedto the endoplasmic reticulum.  Caveolin-1could attract proteins to caveolae the same way that clathrin adaptors attracttransmembrane receptors to coated pits and/or function as a molecular motorthat powers membrane invagination and budding (Liu et al., 2002).  Jiang Liu’s group in 2004 also showed thatouabain induced endocytosis of membrane bound NKA and that this could onlyoccur in the presence of caveolin-1.  Themechanism of how this transport may occur is still unknown.  One possibility would be that endosomal-engulfedNORC may move through the cell across a microtubule cytoskeletal network.

Endocytosis & AutosisNKA regulated,non-apoptotic cell death, termed ‘autosis’, which is induced byautophagy-inducing peptides, starvation, and hypoxia-ischemia, andcharacterized by the disappearance of endoplasmic reticulum and focal swellingof the perinuclear space (Yang et al., 2015). The lysosomal degradation pathway of autophagy plays a crucial role inenabling eukaryotic cells to adapt to environmental stress (Liu et al.,2013).  The mechanisms involved inautosis, however, have yet to be elucidated, one possibility could involveendogenous ouabain as a mediator.

  Cardiacglycosides rescue clonogenic survival of cells that die by autophagy-inducingpeptide or starvation-induced autosis (Liu et al., 2015).  This protective effect has also been seen invivo: during cerebral hypoxia or ischemia – the brain releases an endogenousform of cardiac glycoside (ouabain or endobain) that inhibits NKA (Yang et al,.2013).

Thus, by releasing its own inhibitor of NKA in response tohypoxia–ischemia, the neonatal brain may have developed an important mechanismto reduce autophagy and cell death by autosis (Yang, 2013). With the enlistmentof caveolin-1 and the protective effects of ouabain along with other endogenouscardiac glycosides, NORC may associate with pro- and anti-apoptotic proteinsnot restricted to the cell membrane.Tubulin and Microtubules The transit of theproposed NORC from the membrane to and through the cytoplasm constitutes anotherunknown factor.

  One explanation could bethe transport along a known system of microtubules (MT).  MTs are highly dynamic tubular polymersassembled from cytoplasmic protofilaments of ?/?-tubulin dimers, and areessential for intracellular transport, architectural organization, and forceproduction in eukaryotic cells (Al-Bassam, 2012).  Microtubules (MTs) are formed within cellsvia the polymerization of the ?/?-tubulin units creating a cylindricalstructure