A Putative Cation Channel, NCA-1, and a Novel Protein, UNC-80, Transmit Neuronal Activity in C. elegans

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Abstract
Voltage-gated cation channels regulate neuronal excitability through selective ion flux. NALCN, a member of a protein family that is structurally related to the α1 subunits of voltage-gated sodium/calcium channels, was recently shown to regulate the resting membrane potentials by mediating sodium leak and the firing of mouse neurons. We identified a role for the Caenorhabditis elegans NALCN homologues NCA-1 and NCA-2 in the propagation of neuronal activity from cell bodies to synapses. Loss of NCA activities leads to reduced synaptic transmission at neuromuscular junctions and frequent halting in locomotion. In vivo calcium imaging experiments further indicate that while calcium influx in the cell bodies of egg-laying motorneurons is unaffected by altered NCA activity, synaptic calcium transients are significantly reduced in nca loss-of-function mutants and increased in nca gain-of-function mutants. NCA-1 localizes along axons and is enriched at nonsynaptic regions. Its localization and function depend on UNC-79, and UNC-80, a novel conserved protein that is also enriched at nonsynaptic regions. We propose that NCA-1 and UNC-80 regulate neuronal activity at least in part by transmitting depolarization signals to synapses in C. elegans neurons. Neurons communicate to their targets through synapses that are activated by the electrical signals conveyed along neuronal processes. The tightly regulated ion flux across the cell membrane drives the generation of these electrical signals; it is therefore important to identify ion channels that regulate the excitability of neurons. In the C. elegans nervous system, we reveal that a putative channel complex, consisting of ion-conducting, pore-forming proteins called NCAs and two auxiliary components called UNC-79 and UNC-80, regulates neuronal function. We first show that an increase or decrease of the activity of this channel causes physiological changes that indicate corresponding alterations in neuronal activity. We then demonstrate by in vivo calcium imaging that the NCA channel, localizing along axons, specifically regulates excitation of synapses. We speculate that this channel participates in the propagation of electric signals that activate synapses.