Mechanisms Underlying Influence of Bioelectricity in Development

Could these two different variables—time to threshold calcium level or final amplitude of calcium oscillation—encode different information? More work needs to be done on mapping the tissue wide patterns of bioelectrical signaling, the regions of calcium oscillation propagation, and developmental processes to broaden our understanding of how bioelectrical signaling may coordinate development at a tissue wide level.

While much progress has been made in the field of developmental bioelectricity, there are still barriers that must be addressed. One difficulty is the many overlapping roles of ions, particularly calcium, in cell processes essential to development. Calcium acts as a messenger in a variety of developmental processes: regulating cell death, the cell cycle, cell polarity, migration and well-established developmental signaling pathways. Because many of these pathways impinge upon on the others attributing changes in developmental outcomes to specific pathways is difficult. More work needs to be done within controlled contexts such as cell culture systems to understand how calcium specifically impacts recognized signaling pathways apart from its impact on cell death and the cell cycle.

Another difficulty in elucidating the role of ion channels in development is that there is a limited ability to control a single ionic pathway without impacting others. Levels of calcium, potassium, sodium, and chloride all intersect with each other, which the levels of each ion impacting the levels of the others, making it difficult to distinguish roles of specific ion channels and ions. Much of the research in the field of developmental biology has focused on disruption or manipulation of specific individual genes to elucidate the roles of individual proteins. In the field of bioelectricity, it might be more beneficial to focus on overall changes in transmembrane potential and calcium oscillations rather than on specific channels as it is likely that these changes, rather than the specific ion channels themselves, are what regulate development.

Gaining a greater understanding of bioelectrical signaling will elucidate another complex pathway by which cells may coordinate development. This greater understanding of development is necessary to potentially open new avenues within medicine. Ion channel signaling is dependent on a network of interdependent ion channels and is not necessarily dependent on single individual types of channels. This means that pharmaceuticals that elicit changes in overall cell polarization rather than by acting on specific channels, could potentially regulate larger changes in morphogenesis which has not been previously possible. In regenerative medicine after trauma, for example, an understanding of bioelectric signaling may provide new avenues of directing tissue growth and healing. “Electroceuticals,” devices or drugs that induce bioelectrical changes in tissues, are already being investigated as potential mechanisms in medicine to improve healing (Levin et al., 2019).

In summary, ion channels play an essential role in development with bioelectricity regulating cell death, the cell cycle, proliferation, cell polarity, migration, and the canonical developmental signaling pathways. A greater understanding of the mechanisms by which ion channels act will reveal new avenues in medicine by which developmental disorders may be treated.

We are grateful for funding from NIH-NIDCR R01DE025311 and NSF-IOS 1945916 and NSF-IOS 1354282 to EAB. EB would like to thank childcare providers for their heroic efforts during the Covid-19 pandemic.

LG wrote the first draft of the manuscript and created the figures. EB made suggestions for the content and edited the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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