Cell cycle modulation of gap junction permeability and intercellular heterogeneity
Cell cycle stage changes the electrical state of a cell and, according to Glen, McDevitt and Kemp (2018), how freely it exchanges material with its neighbours. They proposed that, because gap junction connectivity varies with the cycle, a dividing population is a source of dynamic heterogeneity.8 Earlier work had already shown that membrane voltage shifts as cells pass through the cycle.34
- Earliest held
- 1926, Crile, G. W.
- Most discussed in
- Dynamic intercellular transport modulates the…, 2018
- In the library
- 234 passages in 59 works
- Rewritten
- 2026-10-23
Early links to growth
Crile (1926) recorded that observers agreed the most rapid nuclear growth comes shortly before mitosis, while cytoplasmic growth stays comparatively steady.1 That is a structural link between timing in the cycle and cell state. Urrego and colleagues (2014) describe an early finding that resting membrane potential correlates with mitotic activity. Holding Chinese hamster ovary cells at a fixed hyperpolarized value completely inhibited DNA synthesis, and cycling returned when the potential was released.2 Muscle cells and neurons, which are very hyperpolarized, typically show little or no mitotic activity.2
Voltage through the cycle
Rao and colleagues (2015) credit Clarence Cone with observing in sarcoma cells a transient hyperpolarization before mitosis, followed by rapid depolarization through M phase.3 Desoyer and colleagues (2026) give a staged summary: quiescent cells are generally hyperpolarised, depolarisation accompanies G1 entry, hyperpolarisation supports S phase, and depolarisation rises again at G2/M.4 The accounts differ in where they place the changes around mitosis. For a mechanism, Urrego and colleagues describe loss of Kv10.1 K+ conductance at G2/M in Xenopus oocytes, which may produce the depolarization seen in mitosis.5 Sundelacruz, Levin and Kaplan (2008) cite a fibroblast study in which NHE1 activity raised intracellular pH and set the timing of G2/M.6
Nocodazole as a tool
Nocodazole interferes with microtubule polymerization.7 Vandenberg, Pennarola and Levin (2011) used it in Xenopus embryos as a cytoskeletal reference drug when testing whether vibration disrupts left-right patterning through the same pathway.7 Glen and colleagues used it for a different purpose. They arrested cells at G2/M, removed the drug, and sampled before, immediately after, and 45 minutes after treatment. This gave asynchronous, G2/M-synchronized and mixed G1 and G2/M populations.8 They noted that microtubule depolymerization can affect other cellular processes. To limit this, they identified mitotic cells with Hoechst staining instead of relying on the drug alone.8
Transport by cell cycle stage
Glen and colleagues measured recovery constants for intercellular transport. The asynchronous population gave a unimodal distribution, mostly S-phase cells at about 60%. Mitotic cells had recovery constants about 50% larger on average, meaning slower transport, which the authors say agrees with earlier literature.9 The recovered population mostly showed fast transport. From this the authors deduced that G1 is fast and G2/M slow.9 Rounded cell shape matched each slow case. On this basis, they argue that the cycle creates changing differences in connectivity within a pluripotent network.89
All observers are agreed that the most rapid nuclear growth occurs shortly before mitosis.
Crile, G. W., 1926 · A Bipolar Theory of Living Processes · open at passage 519activity of the Na+-H+ exchanger NHE1 caused an increase in intracellular pH, which regulated the timing of the cell cycle G2/M transition and resulted in cell proliferation
Sundelacruz S, Levin M, Kaplan DL, 2008 · Membrane potential controls adipogenic and osteogenic differentiation of… · open at passage 5we first performed epistasis experiments to determine whether vibration was affecting the same pathway as nocodazole, which interferes with microtubule polymerization
Vandenberg LN, Pennarola BW, Levin M, 2011 · Low frequency vibrations disrupt left-right patterning in the Xenopus embryo · open at passage 18forcing the membrane potential of Chinese hamster ovary cells to a fixed hyperpolarized value completely inhibited DNA synthesis measured as [3H]thymidine incorporation, while cycling was recovered upon release of the potential
Urrego D, Tomczak AP, Zahed F, Stühmer W, Pardo LA, 2014 · Potassium channels in cell cycle and cell proliferation · open at passage 4The resulting net loss of K+ conductance at G2/M transition may be a way to achieve membrane depolarization associated with mitosis.
Urrego D, Tomczak AP, Zahed F, Stühmer W, Pardo LA, 2014 · Potassium channels in cell cycle and cell proliferation · open at passage 20it was observed that Vm underwent a transient hyperpolarization before entering mitosis, followed by a rapid depolarization through the M Phase suggesting that Vm varies through the cell cycle progression
Rao VR, Perez-Neut M, Kaja S, Gentile S, 2015 · Voltage-gated ion channels in cancer cell proliferation · open at passage 4Given the capability of the cell cycle to modulate GJ connectivity and the rapid cycling time of pluripotent cells, we hypothesized that the cell cycle was a source of dynamic heterogeneity within the pluripotent-intercellular network.
Glen CM, McDevitt TC, Kemp ML, 2018 · Dynamic intercellular transport modulates the spatial patterning of… · open at passage 10by establishing that G1-phase and G2/M-phase produce fast and slow transport rates, respectively
Glen CM, McDevitt TC, Kemp ML, 2018 · Dynamic intercellular transport modulates the spatial patterning of… · open at passage 12Quiescent cells are generally hyperpolarised; depolarisation accompanies entry into the G1 phase; hyperpolarisation supports DNA synthesis in the S phase; and further depolarisation occurs during the G2/M transition.
Desoyer C, Šupe R, Ghorbanpour S, Goswami D, Khalaj M…, 2026 · Cancer: A bioelectric disease? · open at passage 12