Harnessing acid-sensing ion channel toxins for therapeutic purposes

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PROJECT SUMMARY/ABSTRACT Generalized anxiety and panic disorder are debilitating disorders resulting in severe social and economic impact for patients. Antidepressants and benzodiazepines are the current frontline pharmacological treatments but both medication types come with undesirable side effects, well- documented compliance issues and/or abuse potential. Acid-sensing ion channels (ASICs) represent a new drug target and potential treatment avenue for these conditions. ASICs are a family of pH- activated ion channels found throughout the nervous system, being especially enriched in the amygdala. Genetic deletion of ASIC genes in mice results in several anxiolytic phenotypes including greater exploration in open field maze experiments, attenuated freezing in tone-foot shock pairing and the complete loss of long-term potentiation between synapses in the lateral amygdala. Pharmacological inhibition of ASICs using the highly selective psalmotoxin1 peptide also produces anxiolytic effects when injected into rodents. Unfortunately, psalmotoxin1 does not readily cross the blood-brain barrier and there are currently no high affinity/high selectivity small molecule ASIC drugs. Here we propose to furnish novel drugs leads using newly described ASIC selective toxins. To do this we will first combine electrophysiology and high throughput assays to map interactions between human ASIC1a and a selective toxin. Subsequently, we will use molecular modelling to predict hASIC1a-toxin binding sites. Finally, we will test these proposed binding sites using electrophysiology and chemical crosslinking. Together, these aims will identify the binding sites and mechanism of action of high affinity ASIC selective toxins, providing foundational insight into the channel while expanding the therapeutic armamentarium. Given the involvement of ASICs in anxiety disorders, and a myriad of other conditions, such pharmacological advances could have broad health care implications.