Acid-sensing ion channels (ASICs) are pH-dependent cation channels that are widely expressed throughout the central and peripheral nervous system. They are involved in numerous acidosis-related pathologies including pain, inflammation, and stroke1 . ASIC1a, the primary acid sensor in mammalian brain, is an important player in the regulation of ionic homeostasis following ischemic injury, and knockout of ASIC1a markedly reduces infarct size following ischemic stroke2 .
As part of our ongoing program to develop subtype-specific modulators of ASICs, we discovered several venom peptides, derived from both spiders and snakes that potently and specifically inhibit ASIC1a. The most potent peptide, isolated from an Australian spider, inhibits human ASIC1a with a picomolar IC50, which is 10-fold more potent than any previously described inhibitor of this channel. This peptide (SVP) acts as a gating modifier that "pushes" ASIC1a into a non-conducting desensitised state. Moreover, unlike other characterised ASIC1a blockers, which are reversible, the effect of SVP is not as easily reversible.
We evaluated two spider-venom-derived ASIC1a blockers in a rat model of stroke. We will demonstrate that either peptide, administered hours after middle cerebral artery occlusion, markedly reduces infarct size and neurological deficits in stroked animals without inducing adverse effects on motor activity. This effect is specific for ASIC1a blockade as a mutated peptide did not induce the same protective activity.