Neuromuscular paralysis by the basic phospholipase A 2 subunit of crotoxin from Crotalus durissus terrificus snake venom needs its acid chaperone to concurrently inhibit acetylcholine release and produce muscle blockage

Cavalcante, Walter Luís Garrido; Noronha‐Matos, José Bernardo; Timóteo, M. Alexandrina; Fontes, Marcos R.M.; Gallacci, Márcia; Correia-de-Sá, Paulo

doi:10.1016/j.taap.2017.08.021

Cited by 25 publications

(27 citation statements)

References 44 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A transient initial facilitation followed by a sustained decay of transmitter release, is observed. Monomer and dimer reduce nerve-evoked radiolabeled-ACh release by 60% and 69%, respectively, but only the crotoxin heterodimer decreased the amplitude of nerve-evoked muscle twitches [19]. This model is also consistent with in vitro studies of C. durissus crotoxin [113].…”

Section: Is Pla 2 and Arachidonic Acid Sufficient To Cause Synaptic Fsupporting

confidence: 83%

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

Bickler

2020

Toxins

View full text Add to dashboard Cite

The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, inflammation, coagulopathy, cell/organ injury, and disruption of homeostatic mechanisms of normal physiology. In this review, we describe how snakebite is not only a condition mediated directly by venom, but by the amplification of signals dysregulating inflammation, coagulation, neurotransmission, and cell survival. Although venom proteins are diverse, the majority of important pathologic events following envenoming follow from a small group of enzyme-like activities and the actions of small toxic peptides. This review focuses on two of the most important enzymatic activities: snake venom phospholipases (svPLA2) and snake venom metalloproteases (svMP). These two enzyme classes are adept at enabling venom to recruit homologous endogenous signaling systems with sufficient magnitude and duration to produce and amplify cell injury beyond what would be expected from the direct impact of a whole venom dose. This magnification produces many of the most acutely important consequences of envenoming as well as chronic sequelae. Snake venom PLA2s and MPs enzymes recruit prey analogs of similar activity. The transduction mechanisms that recruit endogenous responses include arachidonic acid, intracellular calcium, cytokines, bioactive peptides, and possibly dimerization of venom and prey protein homologs. Despite years of investigation, the precise mechanism of svPLA2-induced neuromuscular paralysis remains incomplete. Based on recent studies, paralysis results from a self-amplifying cycle of endogenous PLA2 activation, arachidonic acid, increases in intracellular Ca2+ and nicotinic receptor deactivation. When prolonged, synaptic suppression supports the degeneration of the synapse. Interaction between endothelium-damaging MPs, sPLA2s and hyaluronidases enhance venom spread, accentuating venom-induced neurotoxicity, inflammation, coagulopathy and tissue injury. Improving snakebite treatment requires new tools to understand direct and indirect effects of envenoming. Homologous PLA2 and MP activities in both venoms and prey/snakebite victim provide molecular targets for non-antibody, small molecule agents for dissecting mechanisms of venom toxicity. Importantly, these tools enable the separation of venom-specific and prey-specific pathological responses to venom.

show abstract

Section: Is Pla 2 and Arachidonic Acid Sufficient To Cause Synaptic Fsupporting

confidence: 83%

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

Bickler

2020

Toxins

View full text Add to dashboard Cite

show abstract

“…PLA2s (EC 3.1.1.4) are a large super-family of lipolytic enzymes that cleave the glycerol backbone of phospholipids, usually in a metal-dependent reaction, to release free fatty acids and lysophospholipids [66]. These products of lipid hydrolysis (i.e., arachidonic and linoleic acid) are cytotoxic [67], as demonstrated by many studies on catalytically active venom PLA2s exerting neurotoxic [68,69], myotoxic [70], anticoagulant [71] and antibacterial activities [72]. A pharmacological effect independent of catalytic activity is also predicted for divergent putative homologs of BnPLA2 in other Hymenoptera, such as A. compressa, which lacks the catalytic site (H34) (Additional file 6: Figure S2 and Additional file 7: Figure S10) [73,74].…”

Section: Discussionmentioning

confidence: 99%

Venomics of the ectoparasitoid wasp Bracon nigricans

Becchimanzi¹,

Avolio²,

Bostan³

et al. 2020

BMC Genomics

View full text Add to dashboard Cite

Background: Venom is one of the most important sources of regulation factors used by parasitic Hymenoptera to redirect host physiology in favour of the developing offspring. This has stimulated a number of studies, both at functional and "omics" level, which, however, are still quite limited for ectophagous parasitoids that permanently paralyze and suppress their victims (i.e., idiobiont parasitoids). Results: Here we present a combined transcriptomic and proteomic study of the venom of the generalist idiobiont wasp Bracon nigricans, an ectophagous larval parasitoid of different lepidopteran species, for which we recently described the host regulation strategy and the functional role of the venom in the induction of physiological changes in parasitized hosts. The experimental approach used led to the identification of the main components of B. nigricans venom involved in host regulation. Enzymes degrading lipids, proteins and carbohydrates are likely involved in the mobilization of storage nutrients from the fat body and may concurrently be responsible for the release of neurotoxic fatty acids inducing paralysis, and for the modulation of host immune responses. Conclusion:The present work contributes to fill the gap of knowledge on venom composition in ectoparasitoid wasps, and, along with our previous physiological study on this species, provides the foundation on which to develop a functional model of host regulation, based both on physiological and molecular data. This paves the way towards a better understanding of parasitism evolution in the basal lineages of Hymenoptera and to the possible exploitation of venom as source of bioinsecticidal molecules.

show abstract

“…Labeling nerve terminals and measuring real-time exocytosis was performed as previously described [36][37][38][39]. Phrenic nervehemidiaphragm preparations (4-6 mm width) were mounted on the stage of an upright epifluorescence microscope (Zeiss Axiophot, Oberkochen, Germany).…”

Section: Real-time Video-microscopy Using the Fm4-64 Fluorescent Dye mentioning

confidence: 99%

“…Fluorescence decay was expressed as a percentage of maximal loading considering that 100% is the fluorescence intensity at zero time. As previously described, nerve-evoked FM4-64 intensity decay reflects synaptic vesicle exocytosis at the nerve terminal [33,[36][37][38][39]41]. hexatrienyl) pyridiniumdibromide (FM4-64) and α-bungarotoxin (α-BTX) were purchased from ThermoFisher Scientific (Waltham, MA, USA).…”

Section: Real-time Video-microscopy Using the Fm4-64 Fluorescent Dye mentioning

confidence: 99%

Tetanic Facilitation of Neuromuscular Transmission by Adenosine A<sub>2A</sub> and Muscarinic M<sub>1</sub> Receptors is Dependent on the Uptake of Choline via High-Affinity Transporters

Castellão-Santana¹,

Abiko²,

Ambiel³

et al. 2018

Pharmacology

Self Cite

View full text Add to dashboard Cite

Background/Aims: In this study, we evaluated the functional impact of facilitatory presynaptic adenosine A_2A and muscarinic M₁ receptors in the recovery of neuromuscular tetanic depression caused by the blockage of high-affinity choline transporter (HChT) by hemicholinium-3 (HC-3), a condition that mimics a myasthenia-like condition. Methods: Rat diaphragm preparations were indirectly stimulated via the phrenic nerve trunk with 50-Hz frequency trains, each consisting of 500–750 supramaximal intensity pulses. The tension at the beginning (A) and at the end (B) of the tetanus was recorded and the ratio (R) B/A calculated. Results: Activation of A_2A and M₁ receptors with CGS21680 (CGS; 2 nmol/L) and McN-A-343c (McN; 3 μmol/L) increased R values. Similar facilitatory effects were obtained with forskolin (FSK; 3 μmol/L) and phorbol 12-myristate 13-acetate (PMA; 10 μmol/L), which activate adenylate cyclase and protein kinase C respectively. HC-3 (4 μmol/L) decreased transmitter exocytosis measured by real-time videomicroscopy with the FM4-64 fluorescent dye and prevented the facilitation of neuromuscular transmission caused by CGS, McN, and FSK, with a minor effect on PMA. The acetylcholinesterase inhibitor, neostigmine (NEO; 0.5 μmol/L), also decreased transmitter exocytosis. The paradoxical neuromuscular tetanic fade caused by NEO (0.5 μmol/L) was also prevented by HC-3 (4 μmol/L) and might result from the rundown of the positive feedback mechanism operated by neuronal nicotinic receptors (blocked by hexamethonium, 120 μmol/L). Conclusion: Data suggest that the recovery of tetanic neuromuscular facilitation by adenosine A_2A and M₁ receptors is highly dependent on HChT activity and may be weakened in myasthenic patients when HChT is inoperative.

show abstract

Neuromuscular paralysis by the basic phospholipase A 2 subunit of crotoxin from Crotalus durissus terrificus snake venom needs its acid chaperone to concurrently inhibit acetylcholine release and produce muscle blockage

Cited by 25 publications

References 44 publications

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

Venomics of the ectoparasitoid wasp Bracon nigricans

Tetanic Facilitation of Neuromuscular Transmission by Adenosine A<sub>2A</sub> and Muscarinic M<sub>1</sub> Receptors is Dependent on the Uptake of Choline via High-Affinity Transporters

Contact Info

Product

Resources

About