Membrane potentials and sodium channels: hypotheses for growth regulation and cancer formation based on changes in...

Based on several convergent lines of investigation, we make two hypotheses which are sufficient to explain many phenomena of growth regulation in both normal and cancer cells. 1. The first hypothesis is that there is a boundary or threshold of resting cell membrane potential that separates normal resting cells from normal proliferating cells and cancer cells. The basis for this in existing literature values of membrane potentials in resting and proliferating cells is established. A discussion of how these differences in potential can be explained focuses on changes in sodium permeability and internal sodium concentration. Of many sodium transfer mechanisms, the sodium channel is emphasized and how increased intracellular transfer may stimulate DNA synthesis. The effects of changing cell junctions, in particular gap junctions, on membrane potentials is also discussed, as well as the indications of altered junctions in tumor cells. The linking factor of the effects of growth factors on both cell junctions and sodium permeability leads to the second hypothesis. 2. Since growth initiation and inhibition involve sodium channels and gap junctions, several phenomena can be explained by postulating that they are one and the same entity. The basis for this hypothesis in existing descriptions of functional and structural similarities is outlined. The possible interchange of these elements in the cell cycle lead to several corollaries consequent to the conservation of their total number. The formation of gap junctions would consume sodium channels, decrease sodium permeability and stop DNA synthesis. Conversely, growth factors may competitively bind to channel-connexon elements, cleave gap junctions, liberate sodium channels to increase sodium permeability, and trigger DNA synthesis. Alterations in the structure of gap junction-channel elements in tumor cells would be sufficient to explain some carcinogenesis.