Rat striatal acetylcholinesterase inhibition by Fasciculin (a polypeptide from green mamba snake venom)

Dajas, Federico; Bolioli, B.; Castelló, María E.; Silveira, Ricardo dos Reis

doi:10.1016/0304-3940(87)90612-4

Cited by 17 publications

(4 citation statements)

References 7 publications

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“…Intriguingly, many of the targets of α-neurotoxins have been identified as ion channels or acetylcholine signaling pathways. For example, FS-2 blocks voltage-gated Ca channels [9]; fasciculin-I blocks acetylcholinesterase [10]; MT2 acts on muscarinic acetylcholine receptors [11]; and α-bungarotoxin inhibits nicotinic acetylcholine receptors (nAChRs) [12]. Although ly6 domain-encoding homologs of qvr / sss have also been identified in the genomes of non-venomous animals [13, 14], in most cases the endogenous binding partners of the corresponding proteins have not been identified.…”

Section: Introductionmentioning

confidence: 99%

SLEEPLESS Is a Bifunctional Regulator of Excitability and Cholinergic Synaptic Transmission

Robinson

Joiner

2014

Current Biology

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Summary Background Although sleep is conserved throughout evolution, the molecular basis of its control is still largely a mystery. We previously showed that the quiver/sleepless (qvr/sss) gene encodes a membrane-tethered protein that is required for normal sleep in Drosophila. SLEEPLESS (SSS) protein functions, at least in part, by upregulating the levels and open probability of Shaker (Sh) potassium channels to suppress neuronal excitability and enable sleep. Consistent with this proposed mechanism, loss-of-function mutations in Sh phenocopy qvr/sss null mutants. However, sleep is more genetically modifiable in Sh than in qvr/sss mutants, suggesting that sss may regulate additional molecules to influence sleep. Results Here we show that SSS also antagonizes nicotinic acetylcholine receptors (nAChRs) to reduce synaptic transmission and promote sleep. Mimicking this antagonism with the nAChR inhibitor mecamylamine or by RNAi knockdown of specific nAChR subunits is sufficient to restore sleep to qvr/sss mutants. Regulation of nAChR activity by SSS occurs post-transcriptionally since the levels of nAChR mRNAs are unchanged in qvr/sss mutants. Regulation of nAChR activity by SSS may in fact be direct, since SSS forms a stable complex with and antagonizes fly nAChR function in transfected cells. Intriguingly, lynx1, a mammalian homolog of SSS, can partially restore normal sleep to qvr/sss mutants, and lynx1 can form stable complexes with Shaker-type channels and nAChRs. Conclusions Together, our data point to an evolutionarily conserved, bi-functional role for SSS and its homologs in controlling excitability and synaptic transmission in fundamental processes of the nervous system such as sleep.

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Section: Introductionmentioning

confidence: 99%

SLEEPLESS Is a Bifunctional Regulator of Excitability and Cholinergic Synaptic Transmission

Robinson

Joiner

2014

Current Biology

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“…The following inhibitors were purchased from Sigma (St. L ouis, MO): edrophonium chloride, tetrahydro-aminoacridine hydrochloride (Tacrine), and propidium iodide. Fasciculin was purified as described previously (Dajas et al, 1987;Karlsson et al, 1984), and the monoclonal antibody 25B1 directed against fetal bovine serum AChE was obtained as described by Gentry et al (1995).…”

Section: Methodsmentioning

confidence: 99%

“…In particular, when fasciculin (a 61 amino acid peptide isolated from mamba venom (Rodriguez Ithurralde et al, 1983;Dajas et al, 1987) was used, a much higher concentration (micromolar) was required to inhibit the amyloid-associated AChE than the free soluble enzyme (nanomolar) (Fig. 6 A).…”

Section: Enzymatic Properties Of the Ache Present In The Ache-a␤ Compmentioning

confidence: 99%

Stable Complexes Involving Acetylcholinesterase and Amyloid-β Peptide Change the Biochemical Properties of the Enzyme and Increase the Neurotoxicity of Alzheimer’s Fibrils

et al. 1998

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Brain acetylcholinesterase (AChE) forms stable complexes with amyloid-␤ peptide (A␤) during its assembly into filaments, in agreement with its colocalization with the A␤ deposits of Alzheimer's brain. The association of the enzyme with nascent A␤ aggregates occurs as early as after 30 min of incubation. Analysis of the catalytic activity of the AChE incorporated into these complexes shows an anomalous behavior reminiscent of the AChE associated with senile plaques, which includes a resistance to low pH, high substrate concentrations, and lower sensitivity to AChE inhibitors. Furthermore, the toxicity of the AChE-amyloid complexes is higher than that of the A␤ aggregates alone. Thus, in addition to its possible role as a heterogeneous nucleator during amyloid formation, AChE, by forming such stable complexes, may increase the neurotoxicity of A␤ fibrils and thus may determine the selective neuronal loss observed in Alzheimer's brain.

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“…Dendrotoxins, which belong to the Kunitz-type serine protease inhibitor protein family, interact with voltage-dependent potassium channels, leading to excitatory effects due to facilitation of the release of acetylcholine and potentiation of its effect at the presynaptic nerve terminal25. In addition, fasciculins, which are inhibitors of acetylcholinesterase (AChE), have been isolated from D. angusticeps venom, and these quite unique AChE inhibitors may induce increased synaptic concentrations of acetylcholine causing fasciculation26. Although many toxins have been isolated and sequenced from Dendroaspis venoms, only the venoms of D. polylepis and D. angusticeps have so far undergone a thorough toxicovenomics analysis2122.…”

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confidence: 99%

High-throughput immuno-profiling of mamba (Dendroaspis) venom toxin epitopes using high-density peptide microarrays

Engmark

Andersen

Laustsen

et al. 2016

Sci Rep

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Snakebite envenoming is a serious condition requiring medical attention and administration of antivenom. Current antivenoms are antibody preparations obtained from the plasma of animals immunised with whole venom(s) and contain antibodies against snake venom toxins, but also against other antigens. In order to better understand the molecular interactions between antivenom antibodies and epitopes on snake venom toxins, a high-throughput immuno-profiling study on all manually curated toxins from Dendroaspis species and selected African Naja species was performed based on custom-made high-density peptide microarrays displaying linear toxin fragments. By detection of binding for three different antivenoms and performing an alanine scan, linear elements of epitopes and the positions important for binding were identified. A strong tendency of antivenom antibodies recognizing and binding to epitopes at the functional sites of toxins was observed. With these results, high-density peptide microarray technology is for the first time introduced in the field of toxinology and molecular details of the evolution of antibody-toxin interactions based on molecular recognition of distinctive toxic motifs are elucidated.

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Rat striatal acetylcholinesterase inhibition by Fasciculin (a polypeptide from green mamba snake venom)

Cited by 17 publications

References 7 publications

SLEEPLESS Is a Bifunctional Regulator of Excitability and Cholinergic Synaptic Transmission

SLEEPLESS Is a Bifunctional Regulator of Excitability and Cholinergic Synaptic Transmission

Stable Complexes Involving Acetylcholinesterase and Amyloid-β Peptide Change the Biochemical Properties of the Enzyme and Increase the Neurotoxicity of Alzheimer’s Fibrils

High-throughput immuno-profiling of mamba (Dendroaspis) venom toxin epitopes using high-density peptide microarrays

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