Characterization of Hearing Loss-Related Mutations in ATP-Activated Ion Channels

Abstract

The P2X family of receptors are trimeric ion channels that open in response to binding of ATP to the extracellular surface of the protein. There are seven genes that encode P2X1 to 7 subunits and when expressed alone, all form functional receptors except P2X6. Structurally, each subunit is comprised of intracellular N and C termini, a large extracellular domain containing the ATP binding site and two α-helical transmembrane (TM) domains that form a pore permeable to cations such as K+, Na+ and Ca2+. These ligand-gated cation channels are expressed throughout the body, but are localized in the central nervous system, peripheral nervous system, skeletal, smooth, cardiac muscle, immune cells and the auditory system. P2X2 receptors are hypothesized to play a role in cochlear adaptation to elevated sound levels and protection from overstimulation. Whole-exome sequencing of individuals with dominantly inherited progressive sensorineural hearing loss (DFNA41) revealed three different mutations of P2X2 receptors: V60L, D273Y and G353R. We are studying how these mutations influence the functional properties of P2X2 receptors, and we will present results showing that two of these produce distinct alterations in how these channels gate.