One isoforms of the protein (Liu et al., 2002).

One proposal combines
the relationship between Bcl-2 protein cytosolic concentrations and Bcl-2 interactions
possibly altered through their reciprocal interaction with NKA.  This interaction would occur due to BH-1 and
BH-3 motifs, previously identified upon sequence analysis of crystalized NKA
(Lauf et al., 2013).  These putative
motifs found on NKA could interact directly with the pro- and anti-apoptotic
Bcl-2 subfamilies thereby having a direct effect on cell signaling and
survival.  In conjunction with this
theory, a research group in Sweden showed that in rat proximal tubule cells,
ouabain attenuated the imbalance between the pro-apoptotic effects of BAX and its
inhibitor Bcl-XL (Burlaka et al., 2013). 
We propose CTS-driven effects correspond with NKA inhibition and NKA’s
Bcl-2 motifs and possible unveiling of BH-3 motifs that interact within the


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Caveolae were first
identified as flask-shaped, noncoated vesicular membrane invaginations (Liu et
al., 2004).  Caveolins are 21 to 24 kDa
membrane-associated scaffold proteins and the major structural components of
caveolae (Liu et al., 2004). The principal site where one would expect
caveolin-1 to function in membrane traffic is at the caveola (Liu et al., 2002).  Recently, ouabain has been found to initiate endocytosis
of the NKA receptor in proximal tubule cells, but only when caveolin-1 is
present (Liu et al., 2004).  Caveolae are
well known for their unique endocytic properties (Liu et al., 2002).  There are three caveolin genes expressed in
mammals (designated caveolin-1, -2, and -3), and they code for five different
isoforms of the protein (Liu et al., 2002). 
Caveolin typically functions as a scaffold for lipid transport within
the cells interacting with cholesterol creating lipid rafts, which are transported
to the endoplasmic reticulum.  Caveolin-1
could attract proteins to caveolae the same way that clathrin adaptors attract
transmembrane receptors to coated pits and/or function as a molecular motor
that powers membrane invagination and budding (Liu et al., 2002).  Jiang Liu’s group in 2004 also showed that
ouabain induced endocytosis of membrane bound NKA and that this could only
occur in the presence of caveolin-1.  The
mechanism of how this transport may occur is still unknown.  One possibility would be that endosomal-engulfed
NORC may move through the cell across a microtubule cytoskeletal network.

Endocytosis & Autosis

NKA regulated,
non-apoptotic cell death, termed ‘autosis’, which is induced by
autophagy-inducing peptides, starvation, and hypoxia-ischemia, and
characterized by the disappearance of endoplasmic reticulum and focal swelling
of the perinuclear space (Yang et al., 2015). 
The lysosomal degradation pathway of autophagy plays a crucial role in
enabling eukaryotic cells to adapt to environmental stress (Liu et al.,
2013).  The mechanisms involved in
autosis, however, have yet to be elucidated, one possibility could involve
endogenous ouabain as a mediator.  Cardiac
glycosides rescue clonogenic survival of cells that die by autophagy-inducing
peptide or starvation-induced autosis (Liu et al., 2015).  This protective effect has also been seen in
vivo: during cerebral hypoxia or ischemia – the brain releases an endogenous
form of cardiac glycoside (ouabain or endobain) that inhibits NKA (Yang et al,.
2013). Thus, by releasing its own inhibitor of NKA in response to
hypoxia–ischemia, the neonatal brain may have developed an important mechanism
to reduce autophagy and cell death by autosis (Yang, 2013). With the enlistment
of caveolin-1 and the protective effects of ouabain along with other endogenous
cardiac glycosides, NORC may associate with pro- and anti-apoptotic proteins
not restricted to the cell membrane.

Tubulin and Microtubules

The transit of the
proposed NORC from the membrane to and through the cytoplasm constitutes another
unknown factor.  One explanation could be
the transport along a known system of microtubules (MT).  MTs are highly dynamic tubular polymers
assembled from cytoplasmic protofilaments of ?/?-tubulin dimers, and are
essential for intracellular transport, architectural organization, and force
production in eukaryotic cells (Al-Bassam, 2012).  Microtubules (MTs) are formed within cells
via the polymerization of the ?/?-tubulin units creating a cylindrical