Latrotoxin Receptor Signaling Engages the UNC-13-Dependent Vesicle-Priming Pathway in C. elegans

Willson, James K.V.; Amliwala, Kiran; Davis, Andrew; Cook, Alan F.; Cuttle, Matthew F.; Kriek, Neline; Hopper, Neil A.; O’Connor, Vincent; Harder, Achim; Walker, Robert; Holden‐Dye, Lindy

doi:10.1016/j.cub.2004.07.056

Cited by 75 publications

(69 citation statements)

References 37 publications

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“…Using pharmacological approaches and taking advantage of the mutant toxin LTX N4C we have in part delineated the downstream signaling of latrophilin in clonal ␤-cells. The increase in [Ca 2ϩ ] i depends on activation of phospholipase C, and similar pathways have been described previously in synaptosomes, in neurons, in neuroblastoma cells transiently expressing latrophilin, as well as in the case of the recently identified latrophilin-like orthologue in Caenorhabditis elegans (12,13,15,56). In concordance with recordings from pyramidal neurons, the observed release from intracellular stores in MIN6 cells implied the inositol 1,4,5-trisphosphate receptor (13).…”

Section: Discussionsupporting

confidence: 84%

α-Latrotoxin Induces Exocytosis by Inhibition of Voltage-dependent K+ Channels and by Stimulation of L-type Ca2+ Channels via Latrophilin in β-Cells

Lajus

Vacher

Huber

et al. 2006

Journal of Biological Chemistry

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The spider venom ␣-latrotoxin (␣-LTX) induces massive exocytosis after binding to surface receptors, and its mechanism is not fully understood. We have investigated its action using toxin-sensitive MIN6 ␤-cells, which express endogenously the ␣-LTX receptor latrophilin (LPH), and toxin-insensitive HIT-T15 ␤-cells, which lack endogenous LPH. ␣-LTX evoked insulin exocytosis in HIT-T15 cells only upon expression of full-length LPH but not of LPH truncated after the first transmembrane domain (LPH-TD1). In HIT-T15 cells expressing full-length LPH and in native MIN6 cells, ␣-LTX first induced membrane depolarization by inhibition of repolarizing K ؉ channels followed by the appearance of Ca 2؉ transients. In a second phase, the toxin induced a large inward current and a prominent increase in intracellular calcium ([Ca 2؉ ] i ) reflecting pore formation. Upon expression of LPH-TD1 in HIT-T15 cells just this second phase was observed. Moreover, the mutated toxin LTX N4C , which is devoid of pore formation, only evoked oscillations of membrane potential by reversible inhibition of iberiotoxin-sensitive K ؉ channels via phospholipase C, activated L-type Ca 2؉ channels independently from its effect on membrane potential, and induced an inositol 1,4,5-trisphosphate receptor-dependent release of intracellular calcium in MIN6 cells. The combined effects evoked transient increases in [Ca 2؉ ] i in these cells, which were sensitive to inhibitors of phospholipase C, protein kinase C, or L-type Ca 2؉ channels. The latter agents also reduced toxin-induced insulin exocytosis. In conclusion, ␣-LTX induces signaling distinct from pore formation via full-length LPH and phospholipase C to regulate physiologically important K ؉ and Ca 2؉ channels as novel targets of its secretory activity.The black widow spider venom ␣-latrotoxin (␣-LTX) 2 induces massive exocytosis of synaptic vesicles and of large dense core vesicles. This property has been extensively exploited to investigate the molecular mechanisms underlying exocytosis (1, 2). Toxin action requires first the binding to a surface receptor, and three distinct receptors for ␣-LTX have been identified: the latrophilins (LPHs), which contain a large extracellular adhesion molecule domain and a C-terminal portion bearing the signature of G-protein-coupled receptors (3, 4), neurexin Ia and ␤ (2), and the receptor-like protein-tyrosine phosphatase (5). It is generally accepted that the toxin inserts subsequently as a tetramer into membranes to form a stable, cation-permeable pore (6), and the ensuing Ca 2ϩ influx plays a major role in the activation of exocytosis. Indeed, expression of a C-terminally truncated form of LPH lacking all except the first transmembrane domain is sufficient to establish toxin-induced pores leading to calcium influx in epithelial HEK293 cells and sensitization of exocytosis in chromaffin cells (7-9). Although these findings indicate that receptor-mediated signal transduction is not required for the action of ␣-LTX, other observations suggest that pore-mediate...

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Section: Discussionsupporting

confidence: 84%

α-Latrotoxin Induces Exocytosis by Inhibition of Voltage-dependent K+ Channels and by Stimulation of L-type Ca2+ Channels via Latrophilin in β-Cells

Lajus

Vacher

Huber

et al. 2006

Journal of Biological Chemistry

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“…Similarly to 1, emodepside (19) also interacts with the latrophilin-like receptor HC 110R (Saeger et al 2001). It causes flaccid paralysis of nematodes, consistent with a-latroxin-like action, and functional studies indicate that the main target site of 19 is presynaptic (Willson et al 2004). …”

Section: Resultsmentioning

confidence: 93%

Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi–synthetic anthelmintics such as emodepside

et al. 2005

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The 24-membered cyclooctadepsipeptide (CODP) PF1022A, the active metabolite of the fungus imperfectus Mycelia sterilia (Rosellinia sp.) isolated from the plant Camellia japonica in Japan, is described as a powerful broad-spectrum anthelmintic natural product with low toxicity in animals. Further CODPs such as PF1022B, C, D and E have been isolated from the same culture and their structures have been established. Both PF1022A and PF1022E serve as valuable starting materials for the synthesis of semi-synthetic CODP derivatives with improved intrinsic anthelmintic potency and broad-spectrum activity. It was found that in most cases the di-substituted PF1022A derivatives showed a greater (or equal) activity by oral application against the gastrointestinal nematode Haemonchus contortus compared to the corresponding mono-substituted PF1022A analogues as exemplified by emodepside. In order to get additional information on the bioactive conformation, emodepside was transformed into its mono- and tetra-thionated derivatives by isosteric replacement. In the light of the increased efficacy of these derivatives against H. contortus or Trichostrongylus colubriformis, it has been suggested that the asymmetric conformation clearly influences the anthelmintic activity of CODPs. Although useful synthetic pathways are available today for the preparation of the semi-synthetic CODP emodepside, the fermentative production of its bis-para-nitro and bis-para-amino precursors could be the process used for its industrial-scale production in the future.

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“…7) (Willson et al 2004b). This process is negatively regulated through the effect of Gao on DAG kinase.…”

Section: Model Of the Mode Of Action Of Emodepsidementioning

confidence: 96%

Mechanisms of action of emodepside

et al. 2005

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The research of the class of cyclic octadepsipeptides started at the beginning of the 1990s. PF1022A, the starting material of emodepside, is a natural secondary metabolite of the fungus Mycelia sterilia, which belongs to the microflora of the leaves of Camellia japonica. PF1022A consists of four N-methyl-L-leucins, two D-Iactic acids and two D-phenyllactic acids, which build up a cyclic octadepsipeptide with an alternating L-D-L-configuration. Emodepside is a semisynthetic derivative of PF1022A, which contains a morpholine attached in para position at each of both D-phenyllactic acids. Emodepside is efficacious against a variety of gastrointestinal nematodes. Emodepside binds to a presynaptic latrophilin receptor in nematodes. The following presynaptic signal transduction occurs via activation of Gqalpha protein and phospholipase-Cbeta, which leads to mobilization of diacylglycerol (DAG). DAG then activates UNC-13 and synaptobrevin, two proteins which play an important role in presynaptic vesicle-functioning. This finally leads to the release of a currently unidentified transmitter. The transmitter (or modulator) exerts its effects at the postsynaptic membrane and induces a flaccid paralysis of the pharynx and the somatic musculature in nematodes.

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Latrotoxin Receptor Signaling Engages the UNC-13-Dependent Vesicle-Priming Pathway in C. elegans

Cited by 75 publications

References 37 publications

α-Latrotoxin Induces Exocytosis by Inhibition of Voltage-dependent K+ Channels and by Stimulation of L-type Ca2+ Channels via Latrophilin in β-Cells

α-Latrotoxin Induces Exocytosis by Inhibition of Voltage-dependent K+ Channels and by Stimulation of L-type Ca2+ Channels via Latrophilin in β-Cells

Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi–synthetic anthelmintics such as emodepside

Mechanisms of action of emodepside

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