A Novel Toxin that Targets Acid-Sensing Ion Channels to Produce Pain

Abstract

Natural products have served as invaluable keys to unlocking molecular underpinnings of pain sensation. In particular, plant-derived irritants, such as capsaicin, menthol, mustard oil, have proven essential for identifying and/or characterizing excitatory TRP ion channels that play major roles in pain sensation. Animals also possess chemical defense mechanisms to inflict pain in predators. To more fully exploit the rich pharmacopeia of animal toxins, we established an unbiased screen to discover venoms capable of activating specific subpopulations of somatosensory neurons, with the goal of developing novel probes and identifying important physiological targets for pain research and therapeutics. We show that venom from the Texas coral snake - whose bite produces excruciating pain - contains a novel toxin that potently and persistently activates a subset of somatosensory neurons. First, we use biochemical and molecular methods to identify a unique two-component toxin that form a high affinity heteromeric complex. Second, we use electrophysiological and genetic approaches to identify acid-sensing ion channels (ASICs) as the molecular target. Furthermore, behavioral experiments show that toxin-evoked activation of ASIC channels elicits pain by recruiting a canonical population of primary afferent nociceptors that detect thermal and inflammatory pain.