A proton-inhibited DEG/ENaC ion channel maintains neuronal ionstasis and promotes neuronal survival under stress

The nervous system participates in the initiation and modulation of systemic stress. Ionstasis is of utmost importance for neuronal function. Imbalance in neuronal sodium homeostasis is associated with pathologies of the nervous system. However, the effects of stress on neuronal Na+ homeostasis, excitability, and survival remain unclear. We report that the DEG/ENaC family member DEL-4 assembles into a proton-inactivated sodium channel. DEL-4 operates at the neuronal membrane and synapse to modulate Caenorhabditis elegans locomotion. Heat stress and starvation alter DEL-4 expression, which in turn alters the expression and activity of key stress-response transcription factors and triggers appropriate motor adaptations. Similar to heat stress and starvation, DEL-4 deficiency causes hyperpolarization of dopaminergic neurons and affects neurotransmission. Using humanized models of neurodegenerative diseases in C. elegans, we showed that DEL-4 promotes neuronal survival. Our findings provide insights into the molecular mechanisms by which sodium channels promote neuronal function and adaptation under stress.

Automated summary

The nervous system plays a crucial role in systemic stress response and maintaining neuronal sodium homeostasis. Imbalance in neuronal sodium homeostasis is linked to nervous system pathologies, but the effects of stress on this balance are not well understood. This study reveals that the DEG/ENaC family member DEL-4 functions as a proton-inactivated sodium channel in neuronal membranes and synapses, modulating locomotion in Caenorhabditis elegans. Heat stress and starvation influence DEL-4 expression, which in turn affects the expression and activity of stress-response transcription factors and leads to appropriate motor adaptations. Additionally, DEL-4 deficiency affects dopaminergic neurons and neurotransmission, while promoting neuronal survival in models of neurodegenerative diseases. These findings provide insights into the molecular mechanisms underlying the role of sodium channels in neuronal function and adaptation during stress.