From a systematic screening of animal venoms, we isolated a new toxin (APETx2) from the sea anemone Anthopleura elegantissima , which inhibits ASIC3 homomeric channels and ASIC3‐containing heteromeric channels both in heterologous expression systems and in primary cultures of rat sensory neurons. APETx2 is a 42 amino‐acid peptide crosslinked by three disulfide bridges, with a structural organization similar to that of other sea anemone toxins that inhibit voltage‐sensitive Na+ and K+ channels. APETx2 reversibly inhibits rat ASIC3 (IC50=63 nM), without any effect on ASIC1a, ASIC1b, and ASIC2a. APETx2 directly inhibits the ASIC3 channel by acting at its external side, and it does not modify the channel unitary conductance. APETx2 also inhibits heteromeric ASIC2b+3 current (IC50=117 nM), while it has less affinity for ASIC1b+3 (IC50=0.9 μM), ASIC1a+3 (IC50=2 μM), and no effect on the ASIC2a+3 current. The ASIC3‐like current in primary cultured sensory neurons is partly and reversibly inhibited by APETx2 with an IC50 of 216 nM, probably due to the mixed inhibitions of various co‐expressed ASIC3‐containing channels.

Spiders are the most successful venomous animals and the most abundant terrestrial predators. Their remarkable success is due in large part to their ingenious exploitation of silk and the evolution of pharmacologically complex venoms that ensure rapid subjugation of prey. Most spider venoms are dominated by disulfide-rich peptides that typically have high affinity and specificity for particular subtypes of ion channels and receptors. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides, making them a valuable resource for drug discovery. Here we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against a wide range of pathophysiological conditions including cardiovascular disorders, chronic pain, inflammation, and erectile dysfunction.

Venoms are one of the most convergent of animal traits known, and encompass a much greater taxonomic and functional diversity than is commonly appreciated. This knowledge gap limits the potential of venom as a model trait in evolutionary biology. Here, we summarize the taxonomic and functional diversity of animal venoms and relate this to what is known about venom system morphology, venom modulation, and venom pharmacology, with the aim of drawing attention to the importance of these largely neglected aspects of venom research. We find that animals have evolved venoms at least 101 independent times and that venoms play at least 11 distinct ecological roles in addition to predation, defense, and feeding. Comparisons of different venom systems suggest that morphology strongly influences how venoms achieve these functions, and hence is an important consideration for understanding the molecular evolution of venoms and their toxins. Our findings also highlight the need for more holistic studies of venom systems and the toxins they contain. Greater knowledge of behavior, morphology, and ecologically relevant toxin pharmacology will improve our understanding of the evolution of venoms and their toxins, and likely facilitate exploration of their potential as sources of molecular tools and therapeutic and agrochemical lead compounds.

Significance: Six million people die each year from stroke, and 5 million survivors are left with a permanent disability. Moreover, the neuronal damage caused by stroke often triggers a progressive decline in cognitive function that doubles the risk of dementia for stroke survivors. Despite this massive global disease burden, there are no approved drugs for treating the neuronal injury caused to the brain by the oxygen deprivation occurring during an ischemic stroke. The precipitous drop in brain pH resulting from stroke activates acid-sensing ion channel 1a. We show that inhibition of these channels using a “double-knot” spider venom peptide massively attenuates brain damage after stroke and improves behavioral outcomes, even when the peptide is administered 8 h after stroke onset.