Kelly, J.J. (2011) An investigation of the properties and functions of connexins in the mammalian inner ear. Doctoral thesis, UCL (University College London).
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Connexin 26 (Cx26) and Cx30 are the two predominant gap junction constituents expressed in the mammalian cochlea. Mutations in either gene cause hereditary deafness, indicating an essential role for connexins in auditory function. Gap junctions consisting of Cx26 and Cx30 have been implicated in several cochlear processes; however, the precise functions and life-cycle of connexins in the cochlea are poorly defined. Three aspects of inner ear connexin biology were investigated. Most connexins traffic to the plasma membrane (PM) via the conventional secretory pathway. Conflicting data exists for Cx26 trafficking, whereas that of Cx30 had not been previously studied. Trafficking of Cx26 and Cx30 were investigated using stably-transfected HeLa cell lines. Treatment with brefeldin-A (a Golgi-disrupting drug) did not prevent targeting of Cx30 to the PM, whereas Cx26 was strongly inhibited. These data suggest that Cx30 may traffic to the PM via a Golgi-independent pathway, which is in contrast to a Golgi-dependent pathway for Cx26. Gap junctional intercellular communication (GJIC) pathways are hypothesised to support K+ recycling in the cochlea. This study investigated the development of GJIC in the lateral wall (LW) of live rat cochlear slices. Cx26 and Cx30 immunofluorescence revealed a progressive increase of gap junction expression from postnatal day 0 (P0) to P7-P8. Dye-coupling was compartmentalised between P2-P5, but was extensive by P7. These data suggest that GJIC matures several days in advance of hearing onset and provides anatomical evidence of a putative K+-recycling pathway. Finally, Cx30–/– mice are deaf and fail to develop an endocochlear potential (EP). This study investigated the expression of proteins involved in EP generation and found that the potassium channel Kir4.1 was noticeably reduced in the stria vascularis (SV) of Cx30–/– mice. In contrast to a separate study, the SV endothelial barrier was intact. In addition, anatomical analysis was consistent with loss of Cx30 retarding maturation of SV.
|Title:||An investigation of the properties and functions of connexins in the mammalian inner ear|
|Additional information:||Third party copyright material has been removed from the e-thesis.|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Ear Institute|
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