Development of a Soluble Acid-Sensing Ion Channel Extracellular Domain for Novel Drug Design

Stroke is the third leading cause of death and the leading cause of disability in United States. One detrimental result of ischemic stroke is neuronal death within the brain. The acid-sensing ion channel (ASIC) is keenly tuned to sense the ischemic conditions of stroke. The acid-sensing ion channels are proton-activated ion channels. Recently, several ligands were identified that can modulate ASICs in the absence of protons or acidity. These compounds may be the foundation for novel drug design, but detailed structural data of the ligand-ASIC interaction is lacking. The ASIC structure has been solved at high resolution, but was solved without ligands present. Obtaining the full receptor structure with ligands present is challenging and may slow novel drug design. The development of a soluble protein, which includes potential ligand-binding domains, would be advantageous for studying the ligand-receptor interaction. In order to exploit this advantage, we are developing a soluble ASIC1 extracellular domain (ASIC1-ECD) to aid in the development of novel therapies for ischemic stroke. The ASIC1-ECD (amino acids: 72-425) will be purified and crystallized with various ligands present in order to help further identify ligand-receptor interactions. The steps towards this soluble ASIC1-ECD will be described in this presentation.