Emerging evidence for the modulation of exocytosis by signalling lipids

García-Martínez, Virginia; Giménez-Molina, Yolanda; Villanueva, José; Darios, Frédéric; Davletov, Bazbek; Gutiérrez, Luis M.

doi:10.1002/1873-3468.13178

Cited by 15 publications

(12 citation statements)

References 114 publications

(155 reference statements)

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“…This produces an initial facilitation followed by a long-lasting depression of neuromuscular function. This effect most likely involves both vesicle depletion and receptor inactivation as discussed above; i.e., both pre-and post-synaptic inhibition of NMJ function [116]. Consistent with our model, the initial effects of svPLA 2 increase transmitter release in an exuberant and uncontrolled manner, and then produce deactivation of post-junctional receptors.…”

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

confidence: 81%

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

Bickler

2020

Toxins

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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.

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

confidence: 81%

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

Bickler

2020

Toxins

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“…Arachidonic acid and sphingosine are particularly strong enhancers of exocytosis ( 108 , 109 ). More details about interaction between PUFAs and SNARE can be found in the review by Virginia Garcia-Martinez ( 110 ). The second class of molecules regulating membrane repair are RONS.…”

Section: Regulation Of Membrane Repairmentioning

confidence: 99%

Pathogenesis of Multiple Organ Failure: The Impact of Systemic Damage to Plasma Membranes

Kozlov

Grillari

2022

Front. Med.

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Multiple organ failure (MOF) is the major cause of morbidity and mortality in intensive care patients, but the mechanisms causing this severe syndrome are still poorly understood. Inflammatory response, tissue hypoxia, immune and cellular metabolic dysregulations, and endothelial and microvascular dysfunction are the main features of MOF, but the exact mechanisms leading to MOF are still unclear. Recent progress in the membrane research suggests that cellular plasma membranes play an important role in key functions of diverse organs. Exploration of mechanisms contributing to plasma membrane damage and repair suggest that these processes can be the missing link in the development of MOF. Elevated levels of extracellular phospholipases, reactive oxygen and nitrogen species, pore-forming proteins (PFPs), and dysregulation of osmotic homeostasis occurring upon systemic inflammatory response are the major extracellular inducers of plasma membrane damage, which may simultaneously operate in different organs causing their profound dysfunction. Hypoxia activates similar processes, but they predominantly occur within the cells targeting intracellular membrane compartments and ultimately causing cell death. To combat the plasma membrane damage cells have developed several repair mechanisms, such as exocytosis, shedding, and protein-driven membrane remodeling. Analysis of knowledge on these mechanisms reveals that systemic damage to plasma membranes may be associated with potentially reversible MOF, which can be quickly recovered, if pathological stimuli are eliminated. Alternatively, it can be transformed in a non-resolving phase, if repair mechanisms are not sufficient to deal with a large damage or if the damage is extended to intracellular compartments essential for vital cellular functions.

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“…The role of lipids in exocytosis in neurons and neuroendocrine cells has been evolving dramatically in the last years to pass from being considered as merely structural components to a more active role in the direct regulation of the secretory molecular machinery [87][88][89].…”

Section: Discussionmentioning

confidence: 99%

Vesicle Fusion as a Target Process for the Action of Sphingosine and Its Derived Drugs

Villanueva

Giménez-Molina

Davletov

et al. 2022

IJMS

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The fusion of membranes is a central part of the physiological processes involving the intracellular transport and maturation of vesicles and the final release of their contents, such as neurotransmitters and hormones, by exocytosis. Traditionally, in this process, proteins, such SNAREs have been considered the essential components of the fusion molecular machinery, while lipids have been seen as merely structural elements. Nevertheless, sphingosine, an intracellular signalling lipid, greatly increases the release of neurotransmitters in neuronal and neuroendocrine cells, affecting the exocytotic fusion mode through the direct interaction with SNAREs. Moreover, recent studies suggest that FTY-720 (Fingolimod), a sphingosine structural analogue used in the treatment of multiple sclerosis, simulates sphingosine in the promotion of exocytosis. Furthermore, this drug also induces the intracellular fusion of organelles such as dense vesicles and mitochondria causing cell death in neuroendocrine cells. Therefore, the effect of sphingosine and synthetic derivatives on the heterologous and homologous fusion of organelles can be considered as a new mechanism of action of sphingolipids influencing important physiological processes, which could underlie therapeutic uses of sphingosine derived lipids in the treatment of neurodegenerative disorders and cancers of neuronal origin such neuroblastoma.

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Emerging evidence for the modulation of exocytosis by signalling lipids

Cited by 15 publications

References 114 publications

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

Pathogenesis of Multiple Organ Failure: The Impact of Systemic Damage to Plasma Membranes

Vesicle Fusion as a Target Process for the Action of Sphingosine and Its Derived Drugs

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