Gap junctions and cochlear homeostasis

Abstract

Gap junctions play a critical role in hearing and mutations in connexin genes cause a high incidence of human deafness. Pathogenesis mainly occurs in the cochlea, where gap junctions form extensive networks between non-sensory cells that can be divided into two independent gap junction systems, the epithelial cell gap junction system and the connective tissue cell gap junction system. At least four different connexins have been reported to be present in the mammalian inner ear, and gap junctions are thought to provide a route for recycling potassium ions that pass through the sensory cells during the mechanosensory transduction process back to the endolymph. Here we review the cochlear gap junction networks and their hypothesized role in potassium ion recycling mechanism, pharmacological and physiological gating of cochlear connexins, animal models harboring connexin mutations and functional studies of mutant channels that cause human deafness. These studies elucidate gap junction functions in the cochlea and also provide insight for understanding the pathogenesis of this common hereditary deafness induced by connexin mutations.

Fig. 1

(a) A paraffin section of the guinea pig cochlea stained with hematoxylin and eosin. The perilymphatic space is composed of the scala vestibuli (SV) and scala tympani (ST), and contains high levels of sodium and low levels of potassium ions. Endolymph is present in the scala media (SM), and contains high levels of K⁺ and low levels of Na⁺. I, type I fibrocytes of the spiral ligament; II, type II fibrocytes of the spiral ligament; IHC, inner hair cells; L, spiral limbus; OHC, outer hair cells; RM, Reissner’s membrane; SSZ, suprastrial zone; StV, stria vascularis. Bar = 100 lm. (b) Thin section electron micrograph of a typical gap junction (arrowheads) between supporting cells in the guinea pig organ of Corti. Bar = 100 nm. (c) Freeze-fracture electron micrograph of a typical gap junction (arrow) between supporting cells of the guinea pig organ of Corti. Gap junctions are clusters of homogeneous intramembranous particles, connexons, in the protoplasmic fracture face of the plasma membrane. Bar = 100 nm.

Fig. 2

Schematic illustration of a potassium ion recycling mechanism in the mammalian cochlea. There are two independent gap junction systems, the epithelial cell gap junction system and the connective tissue cell gap junction system in the cochlea. Potassium ions, which play a pivotal role in the mechanoelectrical sound transduction process in the cochlea, are recycled via these two gap junction systems. BC, basal cells; HC, hair cells; IC, intermediate cells, MC, marginal cells; RC, root cells; SC, supporting cells; Type 1 FC, type I fibrocytes; Type II FC, type II fibrocytes. This illustration is modified with permission from Kikuchi et al. (2000a).