Theraphosid venom

Text by Tobias J. Hauke, Volker Herzig and Julian Kamzol & illustrations by Tobias J. Hauke

Venom composition and mechanism of action

Spider venoms are complex cocktails of hundreds to thousands of different chemical molecules. Amongst these are compounds with low molecular masses such as salts, amines or amino acids and large proteins and enzymes, respectively. But the main active components of most spider venoms are typically in the intermediate mass range (~ 1-10 kDa) containing the so-called peptides. More than 1,000 peptides can be present in the venom of a single spider species (Palagi et al., 2013). And peptides that are rich in cysteines (= an amino acid with a thiol group) are the most important amongst them. Cysteine residues enable crosslinks between otherwise linear peptides, which result in a three-dimensional structure that increases the peptide stability. These “cysteine-rich” peptides mostly target ion channels (Kuhn-Nentwig et al., 2011). Ion channels are special pores in biological cell membranes (which separate the interior and exterior of cells) that allow the passage of charged particles (i.e. ions). The intracellular milieu is more negatively charged, whereas the extracellular milieu is more positively charged. This results in an electric charge, the so-called membrane potential that is mostly influenced by different concentrations of sodium, potassium, calcium and chloride ions. When ion channels open, a charge equalisation takes place and the ions diffuse from the side of the membrane with the higher concentration to the side with the lower concentration. This forms the basis for the transmission of stimuli and information in nerve and muscle cells. The opening state of ion channels can be influenced by the membrane potential or by chemical substances that bind to the channel (Silbernagl & Despopoulos, 2007). Hence, by acting on ion channels, spider toxins can disrupt the signal transduction in living organisms and provide an effective way to paralyse potential prey, e.g. by blocking respiration or skeletal muscles. In this manner also theraphosid venoms exhibit a neurotoxic mode of action with most known toxins acting on ion channels (including voltage-gated potassium, calcium and sodium channels, mechanosensitive channels, transient receptor potential channels, and acid-sensing ion channels; Herzig & King, 2013).

Theraphosid venom toxins for the study and treatment of pain

Although Theraphosids are mostly considered harmless for humans, their venoms have been extensively studied, as their large size and commercial availability in the pet trade facilitate the accessibility of larger venom quantities. For venom extraction, the base segments of the chelicerae are stimulated by a mild electrical current and the extracted venom is collected in suitable containers. Many studies on spider venoms aim to explore new bioactive compounds that might be used as lead structures for future drugs. About 450 peptidic venom toxins are currently known from Theraphosid spiders, of which about half were isolated particularly from members of the Asian genus Haplopelma. Theraphosid toxins represent about one third of all known spider peptide toxins (Herzig et al., 2011). Most of the characterized toxins are “cysteine-rich” peptides that act on ion channels in the nervous system. Some toxins that exhibit subtype selectivity for certain voltage gated sodium channels (Na_V) were shown to have analgetic effects and are therefore considered as lead compounds for the development of new painkillers (Saez et al., 2010). For example μ-theraphotoxin-Hd1a, a toxin isolated from the venom of the Asian tarantula species Haplopelma doriae, selectively inhibits human Na_V 1.7 subtype (hNa_V 1.7) (Klint et al., 2015). Since the discovery that a “loss-of-function“ mutation in the gene encoding for hNa_V 1.7 leads to a complete absence of the sensation of pain (Cox et al., 2006), this ion channels evolved as an interesting molecular target for novel analgesics. Using another peptide toxin isolated from the venom of the African tarantula species Heteroscodra maculata, the previously unknown role of Na_V 1.1 in the experience of mechanical pain was recently elucidated (Osteen et al., 2016). Thus Theraphosid venom toxins could represent both lead structures for potentially new painkillers and molecular tools for elucidating new molecular targets for the treatment of pain.

Cited literature:

Cox, J. J.; Reimann, F.; Nicholas, A. K.; Thornton, G.; Roberts, E.; Springell, K.; Karbani, G.; Jafri, H.; Mannan, J.; Raashid, Y.; Al-Gazali, L.; Hamamy, H.; Valente, E. M.; Gorman, S.; Williams, R.; McHale, D. P.; Wood, J. N.; Gribble, F. M. & Woods, C. G. (2006). An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898.

Herzig, V.; Wood, D. L. A.; Newell, F.; Chaumeil, P.-A.; Kaas, Q.; Binford, G. J.; Nicholson, G. M.; Gorse, D. & King, G. F. (2011): ArachnoServer 2.0, an updated online resource for spider toxin sequences and structures. Nucleic Acids Res. 39, 653-657.

Herzig, V. & King, G. F. (2013): The neurotoxic mode of action of venoms from the spider family Theraphosidae. In: Nentwig, W. (Ed.), Spider Ecophysiology. Springer, Heidelberg, 203-215.

Kuhn-Nentwig, L.; Stöcklin, R. & Nentwig, W. (2011): Venom Composition and Strategies in Spiders: Is Everything Possible? Adv. Insect. Physiol. 60, 1-86.

Osteen, J. D.; Herzig, V.; Gilchrist, J.; Emrick, J. J.; Zhang, C.; Wang, X; Castro, J.; Garcia-Caraballo, S.; Grundy, L.; Rychkov, G. Y.; Weyer, A. D.; Dekan, Z.; Undheim, E. A. B.; Alewood, P.; Stucky, C. L.; Brierley, S. M.; Basbaum, A. I.; Bosmans, F.; King, G. F. & Julius, D. (2016): Selective spider toxins reveal a role for the NaV1.1 channel in mechanical pain. Nature 534, 494–499.

Palagi, A.; Koh, J. M. S.; Leblanc, M.; Wilson, D.; Dutertre, S.; King, G. F.; Nicholson, G. M. & Escoubas, P. (2013): Unravelling the complex venom landscapes of lethal Australian funnel-web spiders (Hexathelidae: Atracinae) using LC-MALDI-TOF mass spectrometry. J. Proteomics 80, 292-310.

Saez, N. J.; Senff, S.; Jensen, J. E.; Er, S. Y.; Herzig, V.; Rash, L. D. & King, G. F. (2010): Spider-Venom Peptides as Therapeutics. Toxins 2, 2851-2871.

Silbernagl, S. & Despopoulos, A. (2007): Taschenatlas Physiologie. Thieme, Stuttgart. 441 pages.