Linkage between bioelectric signals and cell cycle control via V_mem changes. (A) Schematic illustrating the linkage of membrane potential modulation to ion channel dynamics during the cell cycle. During G₁/S transition, the membrane potential becomes hyperpolarized relative to the normal resting potential. Potassium channels from the ATP-sensitive, voltage gated and Ca²⁺-activated families become active allowing for potassium efflux from the cell; sodium channels also become activated. During the G₂/S transition the membrane becomes depolarized, and there is a decrease in potassium channel activity. In addition, G₂/M is characterized by the activation of chloride channels and a subsequent efflux of chloride. While the role of potassium channels are the most well-studied in relation to the cell cycle, a number other ion gradients are involved, each contributing to the net membrane potential as described by Goldman-Hodgkin-Katz equation. (B) Membrane voltage in a cell can be altered by a variety of factors, including channel/pump activity in it’s own membrane (cell-autonomous effects), gap junctional communication to neighboring cells of different potential, or nearby electric fields and ion flows from wounded and intact epithelia (the latter two being non-cell-autonomous control mechanisms). In turn, changes in ion flow can be transduced into alterations of the mitotic program by voltage-gated calcium channels and calcium-dependent second-messenger pathways, changes in cell volume, and alterations of transport of mitogens such as serotonin. These can arrive in cells by two voltage-dependent mechanisms: electrophoresis through gap junctions, or changes in the activity of transporters like SERT that are powered by transmembrane potential.

Sample of recursive feedback among physiological parameters and ion channel/pump activity. Bioelectric controls of cell functions are inherently non-linear because channels and pumps produce effects on voltage and pH that in turn regulate those same channels and pumps. Here is shown one example taken from a circuit used in vertebrate left-right patterning. The V-ATPase creates both a pH gradient and contributes to membrane hyperpolarization. At the same time, the H,K-ATPase functions together with a K⁺ channel to regulate V_mem; however, both of these components are themselves voltage- and pH-sensitive. Quantitative models of such networks, which take into account both the molecular biology of components expressed in relevant cells and the time-dependent physiology of the resulting circuit.

Perturbation of growth in Xenopus embryos caused by manipulation of ion channels and electroporation. A variety of mRNAs encoding wild-type and mutant channels were microinjected into frog embryo blastomeres to screen for bioelectrical signals with roles in growth and pattern control. The VSOP proton channel (kindly provided by Yasushi Okamura) (A), the Cx32 gap junction subunit (plasmid kindly provided by Dan Goodenough) (B and C), and the HERG K⁺ channel (plasmid kindly provided by Annarosa Arcangeli) (D) result in ectopic growth and abnormal duplication of body structures such as eyes, sometimes forming extensive fin-like protrusions that are clearly associated with increases in cell growth. (E–E”’) Electroporation of embryos at stage 33, with no DNA, (95 msec interval, 5 msec pulse, 10X repeated) results in significant areas of ectopic growth 24 hours later. Red arrows indicate hyperproliferation.

Membrane voltage levels are not homogenous around the cell surface. Using the voltage-sensitive fluorescent dye DiBAC, early frog embryo blastomeres (A) as well as COS cells in monolayer culture (B) exhibit significant variations of membrane voltage level around the cell surface, indicating that a single V_mem number for a given cell drastically under-estimates the amount of information that can be encoded in the plasma membrane’s physiological state and potentially communicated to neighboring cells. Images courtesy of Dany S. Adams.