Convulxin

Normally, upon injury to the endothelium, collagen mediated GPVI signalling increases platelet formation by thromboxane A2, therefore creating a blood clot.

In case of blood vessel damage, collagen on the extracellular matrix is exposed. As platelets interact with it, an activation signal is sent for aggregation. Platelets interact indirectly with collagen, via the von Willebrand Factor (vWF), which connects the collagen to the platelet GPIb receptor, forcing them close to the site of vessel damage. There, they can interact with receptors on the extracellular matrix, which stimulate adhesion through integrins (heterodimer α₂β₁), and downstream signalling.^[7] GPVI is present as a complex with the Fc receptor (FcR) γ-chain, which gets phosphorylated by SYK as a result of activation by a stimulus.^[8] This generates a downstream signal, leading to platelet activation.

While this is important in case of injury, inappropriate activation of platelets can lead to the formation of clots within the circulation. Such is the case with Convulxin, which can induce a signalling cascade similar to that of collagen. Due to its high affinity, convulxin bind to GPVI and causes clustering of the glycoproteins.

Research has proved that GPlb is not involved in convulxin-induced activation, but that the p62/GPVI collagen receptor is the unique binding site, and protein phosphorylation happens more rapidly and more intensely than in the case of collagen. Furthermore, denatured samples of the toxin containing α, β, or both subunits have been shown not to induce platelet aggregation or tyrosine phosphorylation suggesting that pellet formation requires the native conformation of the protein. However, reduced convulxin subunits still inhibit the effect of collagen since they bind to a common receptor necessary for collagen activation of platelets. .^[2] The free toxin might be evacuated through opsonization via the reticuloendothelial system (for the most part the liver and kidneys) or it might degrade through the lysosomes.^[9]

Therefore, Convulxin acts as an agonist to collagen, inducing platelet activation via GPVI binding, ultimately causing blood clots accumulation in the absence of a homeostatic signal.

Studies^[10] carried out on the toxicity of convulxin show that symptoms are a function of the dose. The effects of the toxin stand out through the sudden and brief duration of the symptoms after exposure.

In mice, low doses (5 μg/animal)  administered intravenously (I.V) elicited tachypnea, followed by apnea, within 20 seconds. The ED₅₀ for brief duration apnea was determined to be 180 μg/kg. Higher doses (10 μg/animal) evoked intense convulsive crisis, and usually ended with the death of the animal. LD₅₀ was determined to be 524 μg/kg. Intraperitoneal (I.P.) administration of up to 200 μg/animal proved to be ineffective.

In cats, I.V. injections of 100 μg/kg showed respiratory disturbances, miosis, salivation, abdominal cramps, nystagmus, loss of equilibrium, convulsions and sometimes a brief phase of hypotonia. The ED₅₀ dose for convulsions is 80 μg/kg. The majority of animals recovered within 30 minutes.

In dogs, the effect of convulxin showed two stages. After I.V. injection of 100-125 μg/kg they became excited, barked and exhibited loss of equilibrium, respiratory disturbances, nystagmus, urination, defecation and vomiting. After recovery, two out of five animals had intermittent crisis of clonic convulsions that appeared after 24 hours and lasted until their death. The other three dogs showed periods of vivid agitation alternating with torpor.

While the lethal dose in humans is not yet known, what has been discovered is that the level of toxic effects depends on the origin of the snake. As for a cure, so far a polyvalent snake antivenom is being used.^[9]