title: Recruitment of sphingosine kinase to presynaptic terminals by a conserved muscarinic signaling pathway promotes neurotransmitter release.
abstract: Sphingolipids are potent lipid second messengers that regulate cell differentiation, migration, survival, and secretion, and alterations in sphingolipid signaling have been implicated in a variety of diseases. However, how sphingolipid levels are regulated, particularly in the nervous system, remains poorly understood. Here, we show that the generation of sphingosine-1-phosphate by sphingosine kinase (SphK) promotes neurotransmitter release. Electrophysiological, imaging, and behavioral analyses of Caenorhabditis elegans mutants lacking sphingosine kinase sphk-1 indicate that neuronal development is normal, but there is a significant defect in neurotransmitter release from neuromuscular junctions. SPHK-1 localizes to discrete, nonvesicular regions within presynaptic terminals, and this localization is critical for synaptic function. Muscarinic agonists cause a rapid increase in presynaptic SPHK-1 abundance, whereas reduction of endogenous acetylcholine production results in a rapid decrease in presynaptic SPHK-1 abundance. Muscarinic regulation of presynaptic SPHK-1 abundance is mediated by a conserved presynaptic signaling pathway composed of the muscarinic acetylcholine receptor GAR-3, the heterotrimeric G protein Gαq, and its effector, Trio RhoGEF. SPHK-1 activity is required for the effects of muscarinic signaling on synaptic transmission. This study shows that SPHK-1 promotes neurotransmitter release in vivo and identifies a novel muscarinic pathway that regulates SphK abundance at presynaptic terminals.
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Chan
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Hu
authors.forename: Derek
authors.initials: D
authors.lastname: Sieburth
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D009116:Muscarine / Q000378:metabolism*; D018721:Muscarinic Agonists / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D013569:Synapses / Q000201:enzymology*; D009435:Synaptic Transmission; D000099157:Sphingosine Kinase
chemical_list: D000109:Acetylcholine; D029742:Caenorhabditis elegans Proteins; D044385:GTP-Binding Protein alpha Subunits; D020662:Guanine Nucleotide Exchange Factors; D009116:Muscarine; D018721:Muscarinic Agonists; D017853:Phosphotransferases (Alcohol Group Acceptor); D011976:Receptors, Muscarinic; D064067:Rho Guanine Nucleotide Exchange Factors; D000099157:Sphingosine Kinase; C477876:GAR-3 protein, C elegans