Function of mambalgin 1 in inhibiting acid-sensing ion channels

Introduction 

Mambalgin 1, a toxin isolated from black mamba venom, is a disulfide-rich polypeptide consisting of 57 amino acids and belongs to the family of three-finger toxins. It is an effective, rapid, reversible inhibitor of ASIC1a or ASIC1b-containing channels in both central and peripheral neurons. The analgesic effect of mambalgin 1 is as strong as that of morphine, but it does not involve opioid receptors. Compared with traditional opioid drugs, it has fewer side effects and has higher therapeutic value.

Pharmacologic action

The X-ray structure of mambalgin-1 has been solved and consists of a three-finger protein fold in which typically three "finger-like" loops containing beta folds are emitted from a central core stabilized by disulfide bonds.. Structurally, mambalgin 1 is directly integrated with the thumb area of cASIC1a. Mambalgin 1 interacts only with the outer surface of the thumb area of cASIC1a, rather than with an acidic pocket, or with the proposed interfacial region in the beta-ball or palm field. A detailed interface analysis showed that Finger I of mambalgin 1 interact with the α4 helix of the cASIC1a thumb domain. The cassi1a mutants (r316A and y317a) located on the α4 helix also showed different inhibitory responses to manbalgin 1 binding.

Function

Asics is involved in a variety of physiological processes, including synaptic plasticity, neurodegeneration, and pain. As a result, Asics has become a new potential therapeutic target for the treatment of mental illness, neurodegenerative diseases and pain. Mambalgin 1 interacts directly with the thumb domain of cASIC1a but not with the acid-sensing pocket as hypothesized through docking analysis based on cASIC1a–PcTx1 crystal structures. At the same time, mambalgin 1 binding was observed to induce an obvious conformational change in the extracellular thumb domain of cASIC1a, which might disrupt the acid-sensing process in cASIC1a.

Pharmacokinetics and metabolism

Mambalgin 1 has undergone clinical trials and has developed venom-based drugs that inhibit neural pathways involved in pain and other sensory pathways. In laboratory experiments using laboratory mice, mambalgin 1 appears to exert clinically significant analgesic effects without side effects (such as respiratory depression and drug tolerance, both associated with opioid analgesics) typically associated with opioid analgesics.

References:

1. Wemmie, J. A., Taugher, R. J., & Kreple, C. J. (2013). Acid-sensing ion channels in pain and disease. Nature Reviews Neuroscience, 14(7), 461-471.