Expression and function of pannexins in the inner ear and hearing

Abstract

Pannexin (Panx) is a gene family encoding gap junction proteins in vertebrates. So far, three isoforms (Panx1, 2 and 3) have been identified. All of three Panx isoforms express in the cochlea with distinct expression patterns. Panx1 expresses in the cochlea extensively, including the spiral limbus, the organ of Corti, and the cochlear lateral wall, whereas Panx2 and Panx3 restrict to the basal cells of the stria vascularis in the lateral wall and the cochlear bony structure, respectively. However, there is no pannexin expression in auditory sensory hair cells. Recent studies demonstrated that like connexin gap junction gene, Panx1 deficiency causes hearing loss. Panx1 channels dominate ATP release in the cochlea. Deletion of Panx1 abolishes ATP release in the cochlea and reduces endocochlear potential (EP), auditory receptor current/potential, and active cochlear amplification. Panx1 deficiency in the cochlea also activates caspase-3 cell apoptotic pathway leading to cell degeneration. These new findings suggest that pannexins have a critical role in the cochlea in regard to hearing. However, detailed information about pannexin function in the cochlea and Panx mutation induced hearing loss still remain largely undetermined. Further studies are required.

Keywords: ATP release; Active cochlear amplification; Cell degeneration; Endocochlear potential; Hearing loss; Inner ear; Pannexin.

Fig. 1

Immunofluorescent labeling for Panx1, 2, and 3 in the cochlea. a-b: Immunofluorescent staining for Panx1. Outer hair cells (OHCs) are visualized by prestin staining (red) in (panel b). c-d: Immunofluorescent staining for Panx2. e-f: Immunofluorescent staining for Panx3. HC: Hensen cell; MO: modiolus; OC: organ of Corti; RM: Reissner’s membrane; SG: spiral ganglion; SLM: spiral limbus; SP: spiral prominence; SPL: spiral ligament; SV: stria vascularis. Scale bar: 50 μm in (a, c), 100 μm in E, 10 μm in (b, d and f). Modified from [18]

Fig. 2

Panx1 deletion induced hearing loss. a: Hearing loss as measured by ABR thresholds, which are significantly increased in Panx1 KO mice. The increase is large at high-frequency range. b: Hearing loss is progressive. **P < 0.001, two-way ANOVA with a Bonferroni correction. Modified from [20, 21]

Fig. 3

Panx1 channels dominate ATP release in the cochlea. Deletion of Panx1 and application of 0.1 mM carbenoxolone (CBX) but not deletion of Cx26 and Cx30, which are predominant connexin isoforms in the cochlea, eliminate ATP release in the cochlea. ATP release was measured in the normal extracellular solution which contains 2 mM Ca⁺⁺. **P < 0.001, one-way ANOVA with a Bonferroni correction. Modified from [21]