Venom peptides targeting acid-sensing ion channel 1: molecular pharmacology and therapeutic potential

LD Rash

School of Biomedical Sciences, The University of Queensland

Proton concentration (pH) is one of the most strictly controlled physiological parameters. It is not surprising then that many organisms have dedicated proton sensors in the form of ion channels and receptors to detect and respond to perturbations in pH. Acid-sensing ion channels (ASICs) are primary proton sensors in mammals and are distributed throughout the central and peripheral nervous system. Decreases in extracellular pH are associated with ischemia, inflammation, tumors and cellular damage, and ASICs play an important role in many pathological conditions such as pain, stroke, multiple sclerosis and traumatic neuronal injury. Thus, the discovery and/or development of subtype-selective ASIC modulators is essential to understand the contribution ASICs make to these debilitating conditions and forms the basis of novel therapeutics. The most potent and selective known inhibitors of ASICs to date are disulfide-rich venom peptides. In this presentation I will show that the ASIC1a/ASIC1b subtype-dependent activity of several venom peptide inhibitors is dictated by a small number of channel residues in the palm region adjacent to alpha-helix 5. Understanding the specific peptide residues that interact with this region allows the possibility to engineer novel inhibitors with unique subtype selectivity profiles. Furthermore, we have discovered a novel spider venom peptide that is the most potent and selective inhibitor of ASIC1a found to date (Hi1a; IC50 of ~500 pM on hASIC1a) and demonstrated its impressive neuroprotective properties when delivered as a single dose up to 8 hours post-ischemic stroke in conscious, spontaneously hypertensive rats. Thus, venom peptides are valuable tools for studying the mechanism of action, pathological role and therapeutic potential of ion channels.