ECTO-NOX proteins are located on the outside surface of the cell. They are not transmembrane proteins and are not firmly anchored in the membrane. ECTO-NOX proteins, like many other ECTO-proteins of the cell surface, are shed and enter into the culture medium or into the circulation (also into saliva, perspiration and urine). They tend to aggregate and probably circulate either as dimers or associated with other proteins (chaperones?) but can also form multimers and even amyloid fibers.
It is not known how ECTO-proteins are functionally associated with the cell surface. They are mostly dissociated by low pH (around pH 5) so that some sort of ionic or salt linkage is implicated. There are also arguments for a receptor that binds ECTO-NOX proteins into functional complexes to allow for transmission of signals to and from the inside of the cell to the ECTO-NOX protein on the outside. Work in progress is designed to identify such a receptor. Since ECTO-NOX proteins especially CNOX carry out a time-keeping function for the cell, some mechanism must exist for the ECTO-NOX proteins to transmit the time-keeping information across the cell membrane toward the cell’s interior. Also, the oscillations of ECTO-NOX proteins at the cell surface are phased by light (by blue light in plants and animals and by red light in plants). ECTO-NOX proteins of themselves do not sense light and must somehow be linked to light-sensing chromophores located in the cell’s interior (cryptochromes or phytochrome). Also ECTO-NOX proteins sense gravity. As gravity sensors they seem to function directly but this information must then be transmitted inward. One could image a rather lengthy and complex signal transduction pathway linking the ECTO-NOX proteins at their external location to the various cellular functions they regulate or that, in turn, regulate (phase) the ECTO-NOX oscillations.
The electron transport function of the ECTO-NOX proteins is very likely necessary to energize the membrane or even to generate the ATP that is used to drive the cell enlargement part of the process. When NADH is oxidized to form NAD+, sufficient energy is released to the membrane to generate at least 3 moles (molecules) of ATP for every mole (molecule) of NADH oxidized. It is unlikely that this energy is simply released as heat but more likely that it is somehow captured either as ATP or as ATP equivalents to be used as needed to drive other processes including cell enlargement.
A second more generalized and more widely recognized function of the electron transport function of the ECTO-NOX proteins is to sustain glycolysis. In large measure, the ATP generated by cells for day-to-day housekeeping chores is generated not by mitochondria which are widely scattered throughout the cell but by soluble glycolytic enzymes of the cytoplasm. These enzymes oxidize glucose and generate ATP from ADP as well as NADH from NAD+. Normally, the NADH is thought to be reoxidized by mitochondrial activity but more and more scientists are coming to realize that an equally major role in the oxidation of glycolytically-generated NADH is via the plasma membrane redox system regulated by the ECTO-NOX proteins as terminal oxidases. The plasma membrane redox system, by oxidizing the glycolytically-produced NADH to reform NAD+, allows glycolytic production of ATP to proceed at a normal rate. Were the NADH not oxidized, glycolysis would stop and the cell would soon run out of ATP. Such a phenomenon is encountered in rho o cells that lack mitochondria. They remain alive, healthy and active as long as plasma membrane redox is active. However, once plasma membrane redox is blocked, the cells quickly run out of ATP and die because they are unable to regenerate the NAD+ necessary to produce more ATP. All the NAD+ is tied up as NADH (NADH constipation) and ATP production is curtailed.
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