Dataset Information

Intracellular Ca²⁺ dynamics in the ALA neuron reflect sleep pressure and regulate sleep in Caenorhabditis elegans.

ABSTRACT: The mechanisms underlying sleep homeostasis are poorly understood. The nematode Caenorhabditis elegans exhibits 2 types of sleep: lethargus, or developmentally timed, and stress-induced sleep. Lethargus is characterized by alternating cycles of sleep and motion bouts. Sleep bouts are homeostatically regulated, i.e., prolonged active bouts lead to prolonged sleep bouts. Here we reveal that the interneuron ALA is crucial for homeostatic regulation during lethargus. Intracellular Ca²⁺ in ALA gradually increased during active bouts and rapidly decayed upon transitions to sleep bouts. Longer active bouts were accompanied by higher intracellular Ca²⁺ peaks. Optogenetic activation of ALA during active bouts caused transitions to sleep bouts. Dysfunction of CEH-17, which is an LIM homeodomain transcription factor selectively expressed in ALA, impaired the characteristic patterns of ALA intracellular Ca²⁺ and abolished the homeostatic regulation of sleep bouts. These findings indicate that ALA encodes sleep pressure and contributes to sleep homeostasis.

SUBMITTER: Miyazaki S

PROVIDER: S-EPMC9189131 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Intracellular Ca2+ dynamics in the ALA neuron reflect sleep pressure and regulate sleep in Caenorhabditis elegans.

Miyazaki Shinichi S Kawano Taizo T Yanagisawa Masashi M Hayashi Yu Y

iScience 20220523 6

The mechanisms underlying sleep homeostasis are poorly understood. The nematode Caenorhabditis elegans exhibits 2 types of sleep: lethargus, or developmentally timed, and stress-induced sleep. Lethargus is characterized by alternating cycles of sleep and motion bouts. Sleep bouts are homeostatically regulated, i.e., prolonged active bouts lead to prolonged sleep bouts. Here we reveal that the interneuron ALA is crucial for homeostatic regulation during lethargus. Intracellular Ca2+</ ...[more]

PMID: 35707721

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Project description:We developed a mathematical model of a hypothetical neuronal signal transduction pathway to better understand olfactory perception in Caenorhabditis elegans. This worm has only three pairs of olfactory receptor neurons. Intracellular Ca(2+) decreases in one pair of olfactory neurons in C. elegans, the AWC neurons, following application of an attractive odor and there is a transient increase in intracellular Ca(2+) following removal of odor. The magnitude of this increase is positively correlated with the duration of odor stimulation. Additionally, this Ca(2+) transient is induced by a cGMP second messenger system. We identified likely candidates for the signal transduction molecules functioning in this system based on available gene expression and physiological data from AWCs. Our model incorporated a G-protein-coupled odor receptor, a G-protein, a guanylate cyclase as the G-protein effector, and a single phosphodiesterase. Additionally, a cyclic-nucleotide-gated ion channel and a voltage-gated ion channel that mediated calcium influx were incorporated into the model. We posited that, upon odor stimulation, guanylate cyclase was suppressed by the G-protein and that, upon cessation of the stimulus, the G-protein-induced suppression ceased and cGMP synthesis was restored. A key element of our model was a Ca(2+)-dependent negative feedback loop that ensured that the calcium increases were transient. Two guanylate cyclase-activating proteins acted on the effector guanylate cyclase to negatively regulate cGMP signaling and the resulting calcium influx. Our model was able to closely replicate in silico three important features of the calcium dynamics of AWCs. Specifically, in our simulations, [Ca(2+)] increased rapidly and reached its peak within 10 s after the odor stimulus was removed, peak [Ca(2+)] increased with longer odor exposure, and [Ca(2+)] decreased during a second stimulus that closely followed an initial stimulus. However, application of random background signal ('noise') showed that certain components of the pathway were particularly sensitive to this noise.

Project description:MCOLN3/TRPML3 is a Ca2+-permeable cation channel that is expressed in multiple subcellular compartments with dynamic localization. Our previous studies suggest that upon macroautophagy/autophagy induction MCOLN3/TRPML3 is recruited and provides Ca2+ for the fusion process in autophagosome biogenesis. However, how intracellular trafficking and the Ca2+ channel function of MCOLN3/TRPML3 are related to autophagy are not known. Here we report that MCOLN3/TRPML3 undergoes palmitoylation at its C-terminal region, which is required for dynamic trafficking and cellular function of MCOLN3/TRPML3 in autophagy. Palmitoylation regulated MCOLN3/TRPML3 surface expression and trafficking, but not channel properties or localization and function of intracellular MCOLN3/TRPML3. Activation of intracellular MCOLN3/TRPML3 induced robust Ca2+ release, which solely increased autophagy in Ca2+- and palmitoylation-dependent manners. Palmitoylation regulated not only intracellular MCOLN3/TRPML3 trafficking to autophagic structures but also autophagic flux in induced autophagy. Importantly, nutrient starvation activated MCOLN3/TRPML3 to release Ca2+ and increased the level of MCOLN3/TRPML3 palmitoylation. Disruption of MCOLN3/TRPML3 palmitoylation, however, abolished the starvation-induced MCOLN3/TRPML3 activation without affecting channel activity. These results suggest that trafficking and channel function of MCOLN3/TRPML3 are regulated in the context of autophagy, and palmitoylation is a prerequisite for the function of MCOLN3/TRPML3 as a Ca2+ channel in autophagosome formation by controlling its trafficking between subcellular compartments. Abbreviations: 17-ODYA, 17-octadecynoic acid; 2-BP, 2-bromopalmitate; BFA, brefeldin A; DN, dominant-negative; GPN, glycyl-L-phenylalanine-beta-naphthylamide; HN, hydroxylamine; KD, knockdown; MCOLN3/TRPML3, mucolipin 3; MS, mass spectrometry; PAT, palmitoyl acyltransferase; PM, plasma membrane; WT, wild type; ZDHHC, a zinc-finger motif and an Asp-His-His-Cys sequence.

Dataset Information

Intracellular Ca²⁺ dynamics in the ALA neuron reflect sleep pressure and regulate sleep in Caenorhabditis elegans.

Publications

Intracellular Ca<sup>2+</sup> dynamics in the ALA neuron reflect sleep pressure and regulate sleep in <i>Caenorhabditis elegans</i>.

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