The molecular action of tarantula toxin may hold clues to better control of chronic pain

Review by Emily Henderson, Bachelor of ScienceNovember 23, 2020

Oversized hairy tarantulas may be unsightly and toxic, but surprisingly, those hunter toxins may retain the answer to better control of chronic pain.

Chinese tarantula bites that catch birds contain needle-like poisons that plunge into the molecular targets of the electrical signaling system of the prey’s nerve cells.

New high-resolution cryo-electron microscopy studies show how Stinger can quickly lock a sodium channel voltage sensor. Sodium channels are small pores in the cell membrane that generate currents and signals that manipulate nerves and muscles. The voltage sensor cannot be activated because it is trapped in a resting position.

Survey results will be published on November 23 Molecular cell, Cell Press journal.

The action of the toxin must be immediate, as the tarantula must fix its prey before taking off. “

William Catalal, Professor of Pharmacology, University of Washington School of Medicine

He was a senior researcher on the study of molecular damage caused by tarantula venom, along with Ning Zheng, a professor of pharmacology and a researcher at the Howard Hughes Medical Institute.

While some may dismiss these tarantulas as ugly, tough and sneaky, medical scientists actually have the ability of poison to trap and shut down the rest of the voltage sensor on voltage-gated sodium channels. I am interested in. As Catterall explains, such studies of toxins from these “big and nasty guys” structure drugs that have the potential to treat chronic pain by blocking sensory nerve signals. It may represent a new approach to designing.

Catterall explained that chronic pain is a difficult disorder to treat. Efforts to seek relief can be a gateway to overdose, addiction, long-term withdrawal, and even death. The development of safer, more effective and non-addictive drugs for pain management is an essential need.

However, because it was difficult to capture the functional morphology of the tarantula toxin-ion channel chemical complex, restructuring small molecule blocking methods of toxins has so far been for better analgesic design. We have avoided molecular biologists and pharmacologists seeking new ideas.

Researchers have overcome this obstacle by designing a chimeric model of sodium channels. Like the mythical centaur, chimeras are made up of parts of two or more species. Researchers have extracted toxin-binding regions from certain types of human sodium channels that are important for pain transmission and imported them from bacteria into the model’s ancestral sodium channels. Since then, Tarantura toxin binds tightly to the receptor site of the sodium channel, providing a clear molecular picture of the composition of the potent toxin.

This result reveals the structural basis of dormant voltage sensor trapping of sodium channels by this toxin.

“Surprisingly, the toxin thrusts the” needle “lysine residue into a negatively charged cluster of voltage sensors, anchoring it in place and interfering with its function,” Catalal said. “Related toxins from various spiders and other arthropod species use this molecular mechanism to fix and kill prey.”

Catterall explained the importance of medical research in this discovery. The human sodium channels placed in the chimeric model are called Nav1.7 channels. He said it plays an important role in the transmission of pain information from the peripheral nervous system to the spinal cord and brain and is therefore a major target for pain treatment.

“This powerful tarantula toxin structure that traps the Nav 1.7 voltage sensor at rest provides a molecular template for future structure-based drug designs of next-generation pain therapies that block Nav1’s function. “I will,” said Catterall. 7 sodium channels. “