Understanding the molecular mechanism underlying the presynaptic toxicity of secreted phospholipases A2: An update

Abstract

β-neurotoxins are enzymes, secreted phospholipases A2, that inhibit neurotransmission in neuromuscular synapses by poisoning the motoneuron. They were reviewed extensively several years ago (Pungerčar and Križaj, 2007). Here we present and critically discuss the most important experimental facts reported since then. Evidence has been presented for specific internalization of β-neurotoxins into the nerve endings of motoneurons, their in vivo binding to some cytosolic proteins, direct action on mitochondria, disruption of Ca(2+) homoeostasis and inhibition of amphiphysin function. New insights have led to a more confident interpretation of the action of these toxins at the molecular level. The most important questions that remain to be answered are listed.

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

“…A number of PLA2s exert strong myotoxic effects which often lead to severe necrosis (Harris and Maltin, 1982;Gutierrez and Ownby, 2003), and many of these toxins also promote inflammation, including edema formation, cytokine production and leukocyte recruitment, pain by inducing thermal allodynia and mechanical hyperalgesia, paralysis through block of neuromuscular transmission and intensify hemorrhage by inhibiting coagulation (Table 1) (Camara et al, 2003;Chacur et al, 2003;Camargo et al, 2008;Teixeira et al, 2011;Lomonte and Rangel, 2012;Harris and Scott-Davey, 2013;Casais-E-Silva et al, 2016;Costa et al, 2017;Zambelli et al, 2017b;Zhang et al, 2017). Neurotoxic effects caused by these toxins, as well as some of their proinflammatory effects, occurs via the modulation of pre-synaptic terminals as well as sensory nerveendings (Camara et al, 2003;Harris and Scott-Davey, 2013;Sribar et al, 2014;Zhang et al, 2017). The PLA2s pre-synaptic effects are characteristic of β-neurotoxins and target the motor nerve terminals at the neuromuscular junction (Sribar et al, 2014;Gutierrez et al, 2017).…”

“…Neurotoxic effects caused by these toxins, as well as some of their proinflammatory effects, occurs via the modulation of pre-synaptic terminals as well as sensory nerveendings (Camara et al, 2003;Harris and Scott-Davey, 2013;Sribar et al, 2014;Zhang et al, 2017). The PLA2s pre-synaptic effects are characteristic of β-neurotoxins and target the motor nerve terminals at the neuromuscular junction (Sribar et al, 2014;Gutierrez et al, 2017). The mechanisms in which certain PLA2s exert their pre-synaptic effects are not fully understood, and the primary targets remain unidentified, although the PLA2 β-bungarotoxin is known to bind to K + channels at the pre-synaptic terminals via an accessory kunitz subunit (Benishin, 1990;Sribar et al, 2014; Figure 1B).…”

“…The PLA2s pre-synaptic effects are characteristic of β-neurotoxins and target the motor nerve terminals at the neuromuscular junction (Sribar et al, 2014;Gutierrez et al, 2017). The mechanisms in which certain PLA2s exert their pre-synaptic effects are not fully understood, and the primary targets remain unidentified, although the PLA2 β-bungarotoxin is known to bind to K + channels at the pre-synaptic terminals via an accessory kunitz subunit (Benishin, 1990;Sribar et al, 2014; Figure 1B). Overall, these presynaptic effects induce robust exocytosis of the neurotransmitters vesicles reserves which consequently lead to the depletion of neurotransmitter release in the neuromuscular junction to promote muscle paralysis (Harris et al, 2000;Sribar et al, 2014;Gutierrez et al, 2017).…”

“…Acute pain through ASIC1 activation (Bohlen et al, 2011) Inflammatory pain, thermal hypersalgesia and mechanical allodynia (Zhang et al, 2017) Excitation of sensory neurons (Bohlen et al, 2011;Zhang et al, 2017) Neurogenic inflammation (Camara et al, 2003;Camargo et al, 2008) Non-neurogenic inflammation Endematogenic and pro-inflammatory (Camara et al, 2003;Casais-E-Silva et al, 2016;Costa et al, 2017) Inhibits platelet aggregation (Teixeira et al, 2011) Phospholipase activity (Gutierrez and Ownby, 2003) Myotoxic (Harris and Maltin, 1982) Pre-synaptic toxin, block of neuromuscular transmission leading to muscle paralysis (Sribar et al, 2014;Gutierrez et al, 2017) SVMP Inflammatory hyperalgesia (Fernandes et al, 2007;Bernardes et al, 2015;De Toni et al, 2015;Ferraz et al, 2015) Endematogenic activity independent of pro-inflammatory mediators (Laing et al, 2003) Cleavage of basement membrane of capillary vessels and endothelial cells adhesion proteins (Gutierrez et al, 2005;Escalante et al, 2011) Procoagulant through activation of prothrombin and Factor X (Takeda et al, 2012;Ainsworth et al, 2018) Inhibition of platelet aggregation (Kamiguti, 2005) Dermonecrotic activity dependent on TNF signaling (Laing et al, 2003) Potential paralysis through inhibition of α-7 neuronal AChR by the cysteine-rich and disintregin-like domains complex (Brust et al, 2013) SVSP Mild mechanical hyperalgesia (Menaldo et al, 2013) Leucocyte migration (Menaldo et al, 2013) Mild edema (Zychar et al, 2010) Procoagulant through activation of prothrombin and factors VII and X (Kini, 2005) Anti-coagulant through activation of Prot...…”

Venoms of related mammal-eating species of taipans (Oxyuranus) and brown snakes (Pseudonaja) differ in composition of toxins involved in mammal poisoning

“…They belong to two major protein families: phospholipases A2 (PLA2) and three-finger toxins (3FTX). Not all PLA2s are neurotoxic, but some induce potent presynaptic neurotoxicity and are called β-neurotoxins [30,31]. Neurotoxic PLA2s from Australian elapid venoms include textilotoxin, taipoxin and paradoxin and display variable protein complex composition [32][33][34].…”