Ion channels produce electrical signals that are critical for the transmission, reception, and integration of information in the nervous system. Ligand-gated ion channels open in response to specific chemicals or neurotransmitters and are especially well adapted for fast chemical-mediated synaptic transmission. The acid-sensing ion channels (ASICs) comprise a family of ligand-gated channels which are activated by acidic changes in extracellular pH. These channels generate voltage insensitive cation currents in many neurons. Mice with disruptions in ASICs have alterations in sensory transduction and deficits in behaviors linked to proper learning and memory. These results suggest that ASIC activity and pH fluctuations play an important role throughout the nervous system. ASICs are members of the DEG/ENaC family of ion channels and each ASIC subunit has two transmembrane domains separated by a large extracellular cysteine-rich region. Individual ASIC subunits associate to form functional channels with distinct biophysical characteristics. The protein domains which determine ASIC characteristics, however, remain largely unknown. The goal of this proposal is to identify the structural and functional determinants of three properties which likely impact ASICs contribution to neuronal signaling: activation, desensitization and neuropeptide modulation. This proposal will use simple expression systems and powerful molecular and electrophysiological methods to characterize the specific protein domains involved in these three properties. The experiments in this proposal are designed to integrate research with a program of teaching and training undergraduate and graduate students. The results from these studies will expand the knowledge of the large extracellular region in DEG/ENaC channels and may eventually aid in the generation of pharmaceuticals targeting ASICs.
