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DEG/ENaC Ion Channels in the Function of the Nervous System: From Worm to Man

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Ion Channels in Biophysics and Physiology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1349))

Abstract

DEG/ENaC channels are voltage-independent Na+/Ca2+ channels that are conserved across species and are expressed in many different cell types and tissues, where they contribute to a wide array of physiological functions from transepithelial Na+ transport, to sensory perception, and learning and memory. In this chapter, we focus on the members of this family that are expressed in the nervous system, grouping them based on their function. Structurally, DEG/ENaC channels are trimers formed by either identical or homologous subunits, each one protruding from the plasma membrane like a clenched hand. Crystallographic studies on chicken ASIC1a in the closed, inactivated, and open states revealed important details about the gating and permeation properties of these channels, and overall they show that the extracellular domain of the channel undergoes large conformational changes during gating. The vast majority of the channel’s extracellular domain is conserved across different members and species; however, key changes including the insertion of extra loops near the finger and palm domains most likely confers gating specificity. Indeed, DEG/ENaC channels are gated by a wide range of stimuli, including mechanical forces, protons, and peptides, owing to the wide array of physiological functions they serve. Interestingly, DEG/ENaC channels are not only expressed in neurons but also in glia. Work in C. elegans is now beginning to shed new light on the role of glial DEG/ENaC in the function of the nervous system and suggests that they may be implicated in controlling ionic concentrations in the extracellular microenvironment. Finally, DEG/ENaC channels can become toxic and cause neuronal death when they are hyperactivated by genetic mutations or prolonged acidosis causing them to contribute to neuronal demise in stroke and ischemia. Taken together, molecular, structural, and behavioral work on DEG/ENaC channels expressed in the nervous system of different species highlights the crucial role of these channels in neuronal function. These data place DEG/ENaC channels in an excellent position for being considered as drug targets for the treatment of several neurological conditions and disorders from pain to epilepsy and ischemia.

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Acknowledgments

I thank all the trainees and colleagues who have contributed to the work which was conducted in my laboratory and is cited in this book chapter. I also thank Nicole Encalada for critical reading of the manuscript. Work in my laboratory has been supported by the National Institute of Health (NS105616, NS106951, NS081259, NS070969, and NS049511) and the American Cancer Society (RGS-09-043-01-DDC).

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  1. Department Physiology and Biophysics, University of Miami, Miller School of Medicine, Miami, FL, USA

    Laura Bianchi

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Correspondence to Laura Bianchi .

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  1. Shenzhen Bay Laboratory, Institute of Molecular Physiology / Virginia Commonwealth University School of Medicine, Shenzhen, Guangdong Province, China

    Lei Zhou

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Bianchi, L. (2021). DEG/ENaC Ion Channels in the Function of the Nervous System: From Worm to Man. In: Zhou, L. (eds) Ion Channels in Biophysics and Physiology. Advances in Experimental Medicine and Biology, vol 1349. Springer, Singapore. https://doi.org/10.1007/978-981-16-4254-8_9

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