Structure and Function of Cochlear Gap Junctions and Implications for the Translation of Cochlear Gene Therapies

Abstract

Connexins (Cxs) are ubiquitous membrane proteins that are found throughout vertebrate organs, acting as building blocks of the gap junctions (GJs) known to play vital roles in the normal function of many organs. Mutations in Cx genes (particularly GJB2, which encodes Cx26) cause approximately half of all cases of congenital hearing loss in newborns. Great progress has been made in understanding GJ function and the molecular mechanisms for the role of Cxs in the cochlea. Data reveal that multiple types of Cxs work together to ensure normal development and function of the cochlea. These findings include many aspects not proposed in the classic K+ recycling theory, such as the formation of normal cochlear morphology (e.g., the opening of the tunnel of Corti), the fine-tuning of the innervation of nerve fibers to the hair cells (HCs), the maturation of the ribbon synapses, and the initiation of the endocochlear potential (EP). New data, especially those collected from targeted modification of major Cx genes in the mouse cochlea, have demonstrated that Cx26 plays an essential role in the postnatal maturation of the cochlea. Studies also show that Cx26 and Cx30 assume very different roles in the EP generation, given that only Cx26 is required for normal hearing. This article will review our current understanding of the molecular structure, cellular distribution, and major functions of cochlear GJs. Potential implications of the knowledge of cochlear GJs on the design and implementation of translational studies of cochlear gene therapies for Cx mutations are also discussed.

GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and function

“…Consistent with this, Gjb2 knockout mice exhibit hearing loss and reduced EP, as reported here and elsewhere. 29 , 30 Additional roles for connexins in the cochlea have been proposed. 13 For instance, gap junctions in SCs within the organ of Corti have been implicated in the generation of DPOAEs as part of active cochlear amplification, and DPOAEs are reduced in Gjb2 mutants.…”

Connexins and the Epithelial Tissue Barrier: A Focus on Connexin 26

“…The auditory canal surface is covered by a simple nonkeratinized squamous epithelium continuous with the lining of the tympanic cavity where CX29 is the predominant connexin expressed. This protein does not form functional gap junctions and is believed to act as a hemichannel in association with voltage-dependent K + channels [ 114 ]. CX26 is expressed in the organ of Corti, the spiral limbus, the stria vascularis, and fibrocytes of the spiral ligament [ 114 ].…”

“…This protein does not form functional gap junctions and is believed to act as a hemichannel in association with voltage-dependent K + channels [ 114 ]. CX26 is expressed in the organ of Corti, the spiral limbus, the stria vascularis, and fibrocytes of the spiral ligament [ 114 ]. The intrical auditory connexin circuit is critical in maintaining the recycling of K + ions in the endolymph enabling auditory function.…”

Global Research on Hereditary Hearing Impairment Over the Last 40 Years: A Bibliometric Study

“… 68 Since it is a relatively small gene, it has been excessively studied and found to encounter many deafness-causing mutations. Despite the great interest in the GJB2 gene as a potential target for gene therapy, germline mutations in mouse GJB2 seem difficult due to death in utero, 69 but due to ongoing active studies on this topic, it is among the most frequently used keywords in articles related to HHI. Since more than 100 different genes that cause genetic hearing loss have been identified, each unique cause will need to be characterized and evaluated for its potential to be the target of successful gene therapy intervention.…”