Nature, published online 3 October 2012; doi:10.1038/nature11494

Credit: NATURE

The intense pain produced by a bite from the Texas coral snake is due to activation of several acid-sensing ion channels (ASICs) in higher organisms, including humans. To identify potential inhibitors of ASICs, Diochot et al. performed a screen of venom from different animals and found that black mamba venom reversibly inhibited ASIC1a. Activity-guided fractionation led to identification of two 57-membered cysteine-rich peptides that the authors named mambalgin-1 and mambalgin-2. The mambalgins inhibit a number of CNS-expressed as well as sensory neuron–specific ASICs. Structural modeling showed that mambalgins resemble the structure of three-finger neurotoxins, stabilized by four disulfide bonds, consistent with the fact that cysteine-rich disulfide-bonded proteins are prevalent components of various snake venoms. Mambalgins bind the channels and modify their affinities for protons. Unlike many toxins, mambalgins do not produce physiological effects such as motor dysfunction, convulsions or death, but they do induce analgesic effects against acute and inflammatory pain, with a potency similar to that of morphine. In a mouse model, ASIC1a and ASIC2a were required for the central analgesic effects, whereas ASIC1b was required for the peripheral analgesic effects. These results indicate that the analgesic effects of mambalgins occur via both primary nociceptors and central neurons through blockade of different ASIC subtypes, and because they do not seem to have the liabilities of other analgesics, mambalgins could prove useful clinically.