INNER EAR GAP JUNCTIONS FOR HEARING

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The long-term goal of this project is to investigate how gap junctional coupling in the organ of Corti contributes to normal hearing. Gap junctional coupling is extensive between the cochlear non-sensory cells. There is no gap junctional coupling between sensory cells (inner and outer hair cells) or between sensory cells and supporting cells. Disturbances of inner ear gap junctions are known to be associated with a high incidence of non-syndromic deafness. Hypothetical functions of gap junctions in the cochlea may involve nutrition, passage of ions and small molecules, and maintaining intracochlear electrochemical gradients. A gap junction channel is composed of connexin proteins; each cell side has 6 connexin subunits. More than 5 connexin genes have been identified in the cochlea. Recording of macroscopic current (containing many channels) has demonstrated that gap junctional coupling in supporting cells has variables transjunctional voltage (Vj) dependence and membrane potential (Vm) dependence. This indicates complex channel constitutions. The specific objective in this proposal is to identify types of gap junctional channels in the cochlear supporting cells by single channel recording. A double voltage clamp technique will be used to record the single channel activity. Transjunctional current will be measured on weakly coupled cell pairs or using uncoupling agents, such as CO2 and octanol, to diminish the cell coupling. Single channel conductance, kinetics and voltage dependence on either cell side will be examined to identify the channel configuration. Acetylcholine (Ach) and cyclic nucleotide will be applied to cells to test the possible gating regulation. The results of these studies may provide clues as to functional gap junctional pathways in the inner ear, and improve our understanding of their contributions to normal mammalian hearing. This information may be clinically relevant for physicians treating patients with deafness induced by connexin mutations.