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Pharmacology
E. Zlotkin, in Comprehensive Molecular Insect Science, 2005
5.6.1.3.3 Naturally secreted venom
The employment of the device used for the collection of scorpion venom immediately after being released by natural stings (Zlotkin and Shulov, 1969) facilitated the analysis of successive venom drops deposited by continuous stinging from individual L. q. hebraeus scorpions. The authentic natural venom was examined for its appearance, protein content, electrophoretic mobility, and paralytic activity to blowfly larvae. It was shown that venom obtained by a series of successive stings changes its appearance in the following order: transparent, opalescent, and viscous secretions. As shown in Table 1, venom collected from individual scorpions demonstrates a wide variability in the number of venom-yielding stings, volume of secreted venom, protein content, and total and specific toxicities. The opalescent venom secretion exhibited the highest total and specific toxicities, in contrast to the transparent venom, which possessed the lowest toxicity. Electropherograms of opalescent and viscous venom secretions closely resemble each other, and both differ from the transparent venom, which had fewer protein bands and lower toxicity (Yahel-Niv and Zlotkin, 1979). A similar diversity in the composition of the successively secreted venom has been recently demonstrated in the venom of the South African scorpion Parabuthus transvaalicus (Buthidae) (Inceoglu et al., 2003) with far-reaching pharmacological implications. As with the Leiurus, the Parabuthus scorpion, when stimulated to sting, first secretes a transparent venom (the prevenom) followed by an opaque (cloudy dense) secretion named venom. Similar to the transparent venom of Leiurus, the prevenom of Parabuthus comprises a relatively small fraction of the volume (22% and 5%, respectively) and of the total protein (25% and 10%, respectively). However, beyond the above similarity, the Parabuthus prevenom reveals a qualitative-fundamental difference. In contrast to the Leiurus transparent venom which possesses only about 3–4% of total toxicity with four times lower specific toxicity than the opaque venom (Table 1), the prevenom of Parabuthus possesses a higher specific toxicity. This toxicity includes higher insect paralysis (×3), mouse lethality (×1.2), and pain production (×3.5) when compared to the dense cloudy venom (Table 2). The potent toxicity of the prevenom is surprising in view of the data presented in Figure 5, showing that it is devoid of the 6–7 kDa long chain polypeptides, which include the potent insect and mammalian neurotoxic polypeptides that affect the voltage-gated sodium channels (see Sections 5.6.2 and 5.6.3). The pharmacologic uniqueness of the prevenom is attributed (Inceoglu et al., 2003) to the presence of a high concentration (80 mM) of K+ salt and certain peptides (Figure 5) that block the voltage-gated rectifying K+ channels. The combined action of these two factors causes a strong local and prolonged depolarization that blocks neuronal conduction and induces pain. Therefore, it appears that the depolarizing effect of high extracellular K+ provided by the prevenom, serves as a pharmacological substitute to the long chain sodium channel gating modifiers. Therefore, it is claimed that by virtue of its unique composition the prevenom economizes the metabolically expensive polypeptides, positively cooperates with the opaque venom, and fulfills an important defensive role as a pain producer (Inceoglu et al., 2003).
It may be concluded that prevenom functions as a separate chemical and functional entity (one scorpion two venoms). This concept challenges the “pharmacological monopoly” of neurotoxic polypeptides and provides an efficient alternative solution to their insecticidal action (Inceoglu et al., 2003). Thus, the transparent venom of Leiurus, due to its low and marginal toxicity, is not equivalent to the prevenom of Parabuthus. It may, however, fulfill a synergistic role with the opaque venom deserving experimental clarification. In contrast to the Parabuthus prevenom, the low toxicity of the first secreted transparent Leiurus venom contradicts the fundamental needs of the slow predator, which has to paralyze its mobile prey in the fastest possible manner. Alternatively, it provides a rational explanation for the phenomenon of multiple stinging of a mobile and vigorous prey, such as the migratory locust (Zlotkin, 1987). In other words, the process of stinging begins with a metabolically cheap venom and continues with a more potent (“expensive”) venom when needed.
The phenomenon of the Leiurus transparent venom is very reminiscent of the observation of Bücherl (1955) who found that drops of electrically milked venom of Tityus serrulatus and T. bahiensis become successively more opalescent and viscous and more toxic to mice. Alternatively, the Parabuthus prevenom phenomenon is supported by an early observation (Miranda et al., 1964), which indicated that the specific toxicity (by weight) of the “manual venom” (see above) was about four times that of the electrically obtained venom.
Finally, given the background of the above-mentioned variability in the successively secreted scorpion venom, it appears that scorpion venom production and secretion is a regulated timed process, enabling precise control of the prey's response and behavior. Such a goal may be achieved, for example, by the preprogramed secretion of insect selective neurotoxins (see Section 5.6.3.2.5).
E. Zlotkin, in Comprehensive Molecular Insect Science, 2005
5.6.1.3.3 Naturally secreted venom
The employment of the device used for the collection of scorpion venom immediately after being released by natural stings (Zlotkin and Shulov, 1969) facilitated the analysis of successive venom drops deposited by continuous stinging from individual L. q. hebraeus scorpions. The authentic natural venom was examined for its appearance, protein content, electrophoretic mobility, and paralytic activity to blowfly larvae. It was shown that venom obtained by a series of successive stings changes its appearance in the following order: transparent, opalescent, and viscous secretions. As shown in Table 1, venom collected from individual scorpions demonstrates a wide variability in the number of venom-yielding stings, volume of secreted venom, protein content, and total and specific toxicities. The opalescent venom secretion exhibited the highest total and specific toxicities, in contrast to the transparent venom, which possessed the lowest toxicity. Electropherograms of opalescent and viscous venom secretions closely resemble each other, and both differ from the transparent venom, which had fewer protein bands and lower toxicity (Yahel-Niv and Zlotkin, 1979). A similar diversity in the composition of the successively secreted venom has been recently demonstrated in the venom of the South African scorpion Parabuthus transvaalicus (Buthidae) (Inceoglu et al., 2003) with far-reaching pharmacological implications. As with the Leiurus, the Parabuthus scorpion, when stimulated to sting, first secretes a transparent venom (the prevenom) followed by an opaque (cloudy dense) secretion named venom. Similar to the transparent venom of Leiurus, the prevenom of Parabuthus comprises a relatively small fraction of the volume (22% and 5%, respectively) and of the total protein (25% and 10%, respectively). However, beyond the above similarity, the Parabuthus prevenom reveals a qualitative-fundamental difference. In contrast to the Leiurus transparent venom which possesses only about 3–4% of total toxicity with four times lower specific toxicity than the opaque venom (Table 1), the prevenom of Parabuthus possesses a higher specific toxicity. This toxicity includes higher insect paralysis (×3), mouse lethality (×1.2), and pain production (×3.5) when compared to the dense cloudy venom (Table 2). The potent toxicity of the prevenom is surprising in view of the data presented in Figure 5, showing that it is devoid of the 6–7 kDa long chain polypeptides, which include the potent insect and mammalian neurotoxic polypeptides that affect the voltage-gated sodium channels (see Sections 5.6.2 and 5.6.3). The pharmacologic uniqueness of the prevenom is attributed (Inceoglu et al., 2003) to the presence of a high concentration (80 mM) of K+ salt and certain peptides (Figure 5) that block the voltage-gated rectifying K+ channels. The combined action of these two factors causes a strong local and prolonged depolarization that blocks neuronal conduction and induces pain. Therefore, it appears that the depolarizing effect of high extracellular K+ provided by the prevenom, serves as a pharmacological substitute to the long chain sodium channel gating modifiers. Therefore, it is claimed that by virtue of its unique composition the prevenom economizes the metabolically expensive polypeptides, positively cooperates with the opaque venom, and fulfills an important defensive role as a pain producer (Inceoglu et al., 2003).
It may be concluded that prevenom functions as a separate chemical and functional entity (one scorpion two venoms). This concept challenges the “pharmacological monopoly” of neurotoxic polypeptides and provides an efficient alternative solution to their insecticidal action (Inceoglu et al., 2003). Thus, the transparent venom of Leiurus, due to its low and marginal toxicity, is not equivalent to the prevenom of Parabuthus. It may, however, fulfill a synergistic role with the opaque venom deserving experimental clarification. In contrast to the Parabuthus prevenom, the low toxicity of the first secreted transparent Leiurus venom contradicts the fundamental needs of the slow predator, which has to paralyze its mobile prey in the fastest possible manner. Alternatively, it provides a rational explanation for the phenomenon of multiple stinging of a mobile and vigorous prey, such as the migratory locust (Zlotkin, 1987). In other words, the process of stinging begins with a metabolically cheap venom and continues with a more potent (“expensive”) venom when needed.
The phenomenon of the Leiurus transparent venom is very reminiscent of the observation of Bücherl (1955) who found that drops of electrically milked venom of Tityus serrulatus and T. bahiensis become successively more opalescent and viscous and more toxic to mice. Alternatively, the Parabuthus prevenom phenomenon is supported by an early observation (Miranda et al., 1964), which indicated that the specific toxicity (by weight) of the “manual venom” (see above) was about four times that of the electrically obtained venom.
Finally, given the background of the above-mentioned variability in the successively secreted scorpion venom, it appears that scorpion venom production and secretion is a regulated timed process, enabling precise control of the prey's response and behavior. Such a goal may be achieved, for example, by the preprogramed secretion of insect selective neurotoxins (see Section 5.6.3.2.5).
