Recruitment of sphingosine kinase to presynaptic terminals by a conserved muscarinic signaling pathway promotes neurotransmitter release

Chan, Jason P.; Hu, Zhitao; Sieburth, Derek

doi:10.1101/gad.188003.112

Cited by 67 publications

(111 citation statements)

References 84 publications

(96 reference statements)

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“…However, dgk‐1 is not exclusively expressed in the nervous system but is also expressed in excretory canals (Nurrish et al ., 1999). Thus, to exclude the involvement of other tissues, testing additional mutants with enhanced synaptic transmission such a cpx‐1(ok1552) or tomo‐1(nu468) is warranted (Hobson et al ., 2011; Chan et al ., 2012). …”

Section: Resultsmentioning

confidence: 99%

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

et al. 2015

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SummaryOxidative stress has long been associated with aging and has recently been linked to psychiatric disorders, including psychosis and depression. We identified multiple antipsychotics and antidepressants that extend Caenorhabditis elegans lifespan and protect the animal from oxidative stress. Here, we report that atypical antidepressants activate a neuronal mechanism that regulates the response to oxidative stress throughout the animal. While the activation of the oxidative stress response by atypical antidepressants depends on synaptic transmission, the activation by reactive oxygen species does not. Lifespan extension by atypical antidepressants depends on the neuronal oxidative stress response activation mechanism. Neuronal regulation of the oxidative stress response is likely to have evolved as a survival mechanism to protect the organism from oxidative stress, upon detection of adverse or dangerous conditions by the nervous system.

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Section: Resultsmentioning

confidence: 99%

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

et al. 2015

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“…Rho regulates many biological functions including actin cytoskeleton dynamics and neuronal development, but less is known about Rho function in mature neurons. In C. elegans, Rho has been reported to stimulate synaptic transmission through multiple pathways [9][10][11]. We recently identified the C. elegans orthologs of the NALCN ion channel, NCA-1 and NCA-2, as downstream targets of a G q -Rho signaling pathway [12].…”

Section: Introductionmentioning

confidence: 99%

Dopamine Negatively Modulates the NCA Ion Channels inC. elegans

Topalidou

Cooper

Pereira

et al. 2016

Preprint

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The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein G q and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the G q -Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit G o signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels. Author summaryDopamine is a neurotransmitter that acts in the brain by binding seven transmembrane receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Neuronal G proteins often function by modulating ion channels that control membrane excitability. Here we identify a molecular cascade downstream of dopamine in the nematode C. elegans that involves activation of the dopamine receptor DOP-3, activation of the G protein GOA-1, and inactivation of the NCA-1 and NCA-2 ion channels. We also identify a G protein-coupled receptor kinase (GRK-2) that inactivates the dopamine receptor DOP-3, thus leading to inactivation of GOA-1 and activation of the NCA channels. Thus, this PLOS Genetics | https://doi.org/10.1371/journal.pgen

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“…S1P signaling controls nervous system development S1P 1 signaling is active in the developing nervous system (42), and both S1P synthesis and S1P 1 expression are required for embryonic neurogenesis (10). In the adult nervous system, multiple S1P receptors are expressed on both neurons and glia (71) and may regulate neurotransmission (72)(73)(74). A key function of S1P 1 and S1P 3 occurs during inflammatory disease processes through the promotion of astrogliosis (75,76).…”

Section: S1p Metabolismmentioning

confidence: 99%

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

Proia¹,

Hla²

2015

J. Clin. Invest.

425

438

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IntroductionBioactive lipids, derived from metabolism of plasma membrane lipids, are important mediators of cellular communication in vertebrates. The appearance of bioactive lipid receptors in the vertebrate genomes (1) was coincident with the increased complexity of circulatory, immune, and nervous systems in evolution, suggesting that vertebrates began to use extracellular signaling of lipid mediators for the regulation of sophisticated organ systems. This Review will focus on the lysosphingolipid sphingosine-1-phosphate (S1P) and how the basic understanding of its metabolism, transport, and signaling functions has revealed its role in the pathogenesis of various diseases and allowed rational therapeutic strategies to advance. S1P metabolismSphingosine, the precursor substrate for the synthesis of S1P, is derived by the hydrolysis of ceramide during the sequential degradation of plasma membrane glycosphingolipids and sphingomyelin (refs. 2, 3, and Figure 1). Even though this occurs in various cell compartments, the bulk of sphingosine is generated by degradation in lysosomes. Indeed, the prominence of this lysosomal catabolism pathway is illustrated by the severity of the sphingolipidoses, a family of genetic disorders in which sphingolipid metabolites accumulate (4). The catabolically generated sphingosine is phosphorylated by either of two sphingosine kinases, SPHK1 and SPHK2, to produce S1P. SPHK1 is largely cytoplasmic and can acutely associate with the plasma membranes (5), phagosomes (6), and endosomal vesicles (7), whereas SPHK2 is present cytoplasmically but is predominately in the nucleus (8).While not strictly required for cellular viability (9), the formation of S1P is essential for organismal development (10). The viability of the single Sphk KO mice (10, 11) indicates that the isozymes can partially compensate for each other during development but have nonoverlapping functions. Once formed intracellularly, S1P takes one of three pathways (Figure 1). In one, the sphingosine moiety of S1P is recycled through ceramide synthesis after dephosphorylation by S1P-specific ER phosphatases, SGPP1 and SGPP2 (12, 13). In some mammalian cells, this pathway can account for greater than half of complex sphingolipid synthesis (14).In a second pathway, S1P is irreversibly degraded by S1P lyase, another ER-resident enzyme, into phosphoethanolamine and hexadecenal (15). This reaction facilitates transfer of substrate from the sphingolipid to the glycerolipid pathway via the conversion of hexadecenal by fatty aldehyde dehydrogenase to hexadecanoate, a precursor of palmitoyl-CoA (16), and by the utilization of phosphoethanolamine for phosphatidylethanolamine synthesis (17, 18).In the third pathway, intracellular S1P is released to the extracellular environment, a process that is highly efficient in rbc (19-21), platelets (22), and endothelial cells (19)(20)(21). A specific S1P transporter, SPNS2, is used in endothelial cells for S1P secretion (23). The precise secretion mechanism in rbc has not been established, but ...

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Recruitment of sphingosine kinase to presynaptic terminals by a conserved muscarinic signaling pathway promotes neurotransmitter release

Cited by 67 publications

References 84 publications

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

Dopamine Negatively Modulates the NCA Ion Channels inC. elegans

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

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