Abstract |
Integration of sensory stimuli to appropriately modulate behavioral responses to environmental
signals is critical for organismal survival. The nervous system initiates and modulates systemic stress
responses ensuing physiological stress. Dopamine signaling is involved in several forms of behavioral
plasticity. At the cellular level, ion homeostasis is of utmost importance for neuronal function, both for
the maintenance of resting membrane potential and for the creation and propagation of action potentials.
Imbalance in neuronal sodium homeostasis is associated with many nervous system pathologies.
However, the effect of stress on neuronal sodium homeostasis, excitability, and survival is not explicit.
In this study we focus on the ENaC/DEG family of sodium channels, specifically the Degenerins
subfamily of Caenorhabditis elegans. Degenerins are expressed mainly in the nervous system and are
implicated in several sensory modalities. Degenerins form transmembrane proteins that span twice the
cytoplasmic membrane and assemble in homo-tetramers or hetero-tetramers to generate sodium
channels. By implementing advanced imaging techniques, we found that DEL-2, DEL-3, and DEL-4
degenerins are expressed in dopaminergic, serotonergic, sensory, or motor neurons. We report that the
ENaC/DEG family member DEL-4 assembles into a proton-inactivated, amiloride-sensitive, homomeric
sodium channel. Distinct types of stress regulate this channel, which then triggers appropriate motor
adaptations and organismal stress responses. DEL-4 operates at the neuronal cell membrane to modulate
Caenorhabditis elegans locomotory behaviour. In Caenorhabtitis elegans the functionality of the
dopamine pathway can be easily assessed by monitoring the locomotory response to environmental food
availability cues, a behavior termed basal slowing. We showed that these ion channel proteins induce
basal slowing response. They act through DOP-2 and DOP-3 dopamine receptors and affect the
signaling at the neuromuscular junction. Limitation of DEL-4 reduces dopamine signaling and
cholinergic neurotransmission at the neuromuscular junction. Concurrently, GABAergic signaling
enhances at the neuromuscular junction.
Heat stress and starvation reduce DEL-4 expression, which in turn adjusts the expression and
activity of key stress response transcription factors, such as HSF-1, DAF-16, and SKN-1. Notably,
comparable to heat stress and starvation, DEL-4 deficiency induces hyperpolarization of dopaminergic
neurons to impact neurotransmission. DELs respond to gustatory stimuli and participate in proton and
serotonin perception. Utilizing two humanized models of Parkinson's and Alzheimer's disease in C.
elegans, we demonstrate that DEL-4 promotes neuronal survival in the context of these proteinopathies. DEL-4 deficiency enhances the degeneration of dopaminergic neurons in aged adults, upon control
conditions, and in Parkinson’s and Alzheimer’s disease models. Our findings provide insight into the
molecular mechanisms via which sodium channels uphold neuronal function and promote adaptation
under stress.
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