Decoding Gating Properties of the Pannexin1 Channel: ATP Release and pH Sensitivity and the Potential Role in Health and Disease

Panx1 is implicated in disorders including epilepsy and ischemia, with roles in important physiological processes including learning, memory and sensory function. In sensory systems, ATP release and purinergic signaling is considered the most important function of Panx1. Here, the function in the olfactory epithelium was investigated using Panx1 knock out mice. Functional analysis in vivo confirmed a role in olfaction suggesting that Panx1 is one of several alternative ATP release pathways. Since epileptic and ischemic events cause extracellular pH changes, the role of Panx1 in pH sensing was explored next. In a cell model Panx1 showed pH dependent channel gating properties. Site directed mutagenesis and high throughput dye uptake tests revealed a conserved domain of the protein as a pH sensor. Further, the critical role of a single histidine residue in this domain was determined. In summary, these studies demonstrate the role of Panx1 in ATP release and pH sensing.