Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X₂in the Auditory System

Abstract

The P2X purinergic receptors are cation-selective channels gated by extracellular adenosine 5'-triphosphate (ATP). These purinergic receptors are found in virtually all mammalian cell types and facilitate a number of important physiological processes. Within the past few years, the characterization of crystal structures of the zebrafish P2X4 receptor in its closed and open states has provided critical insights into the mechanisms of ligand binding and channel activation. Understanding of this gating mechanism has facilitated to design and interpret new modeling and structure-function experiments to better elucidate how different agonists and antagonists can affect the receptor with differing levels of potency. This review summarizes the current knowledge on the structure, activation, allosteric modulators, function, and location of the different P2X receptors. Moreover, an emphasis on the P2X2 receptors has been placed in respect to its role in the auditory system. In particular, the discovery of three missense mutations in P2X2 receptors could become important areas of study in the field of gene therapy to treat progressive and noise-induced hearing loss. J. Cell. Physiol. 231: 1656-1670, 2016. © 2015 Wiley Periodicals, Inc.

Progressive Dominant Hearing Loss (Autosomal Dominant Deafness‐41) and P2RX2 Gene Mutations: A Phenotype–Genotype Study

“…P2RX2 receptors are the first stage in a purinergic hearing adaptation mechanism that provides regulation of sound transduction and auditory neurotransmission . More interestingly, we have shown that among family members heterozygous for P2RX2 p.V60L mutation, noise exposure exacerbated high‐frequency hearing loss in young adults Similarly, P2rx2 ‐null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high‐frequency hearing loss, as in young adults.…”

“…In affected subjects, levels of noise exposure that are nominally safe for other individuals exacerbated high‐frequency hearing loss and accelerated presbycusis . P2RX2 is an ion channel purinoreceptor for adenosine triphosphate (ATP) that is known to be critical to hearing . Among family members heterozygous for P2RX2 p.V60L mutation, noise exposure exacerbated high‐frequency hearing loss in young adults .…”

Recent Advancements in Gene and Stem Cell‐Based Treatment Modalities: Potential Implications in Noise‐Induced Hearing Loss

“…P2RX2 encodes for a receptor protein called P2X2, which is an ATP-gated purinergic receptor expressed in hair cells and SCs in the cochlea (Mittal et al, 2016). Normally, P2X2 receptors in the scala media are activated by ATP influx from noise exposure, effectively creating a shunt to attenuate sound transduction in the IHC and OHC (Housley et al, 2013;Yan et al, 2013;Mittal et al, 2016).…”

Recent Advancements in the Regeneration of Auditory Hair Cells and Hearing Restoration

“…Hearing loss can be caused by both environmental and genetic etiological factors, with the genetic contribution comprising for the majority of the cases (Yan and Liu, 2008; Mittal et al, 2015, 2016; Bolz, 2016; Xia W. et al, 2016). To develop therapies for hearing loss due to genetic etiology, methods for gene transfer into the inner ear by in vivo electroporation have been developed (Wang et al, 2012).…”

“…Hearing loss arises from a diverse array of etiologies, including over stimulation of sensory hair cells, trauma to the head, nerve impingement, ototoxic drugs, autoimmune disease and gene mutations (Mijovic et al, 2013; Furness, 2015; Goodall and Siddiq, 2015; Mittal et al, 2015, 2016; Venkatesh et al, 2015; Ben Said et al, 2016; van As et al, 2016). The goal of this review article is to summarize the recent advancements in restoring the hearing function employing new technologies (Table 1).…”