Role Of Aquaporin Water Channel In Mouse Hearing And Visual Physiology

The aquaporins (AQPs) are a family of small integral membrane proteins that function as water transporters. Tremendous progress has been made in the functional and structural study of aquaporins ever since the first aquaporin was isolated from red cell membrane by Peter Agre in 1992. In mammals, 11 different AQPs have been identified (AQPO-AQPIO) which are expressed in a wide variety of endothelial and epithelial tissures rich in water regulation , as well as those water-transport-unrelated tissures like red, white cell, fat cell and bone.A role for aquaporins (AQPs) in hearing and vision has been suggested from the specific expression of aquaporins in inner ear, retinal and the need for precise volume regulation in epithelial cells involved in neural signal transduction.Using mice deficient in selected aquaporins as controls, we localized AQP1 in fibrocytes in the spiral ligament and AQP4 in supporting epithelial cells (Hensen's, Claudius, and inner sulcus cells) in the organ of Corti. In the eye, strong AQP4 expression was found in Muller cells in retina and fibrous astrocytes in optic nerve.To determine whether aquaporins play a role in hearing and vision, auditory brain stem response (ABR) thresholds and electroretinagram (ERG) were compared in wild-type mice and transgenic null mice lacking (individually) AQP1, AQP3, AQP4, and AQP5. In 4-5-week-old mice in a CD1 genetic background, ABR thresholds in response to a click stimulus were remarkably increased by >12 db in AQP4 null mice compared with wild-type mice (p < 0.001), whereas ABR thresholds were not affected by AQP1, AQP3, or AQP5 deletion. In a C57/bl6 background, nearly all AQP4 null mice were deaf, whereas ABRs could be elicited in wildtype controls. ABRs in AQP4 null CD1 mice measured in response to tone bursts (4-20 kHz) indicated a frequency-independent hearing deficit. Light microscopy showed no differences in cochlear morphology of wildtype versus AQP4 null mice. These results provide the first direct evidence that an aquaporin water channel plays a role in hearing. AQP4 may facilitate rapid osmotic equilibration in epithelial cells in the organ of Corti, which are subject to large K~+ fluxes during mechano-electric signal transduction. Significantly reduced ERG b-wave protentials were recorded in 10-month-old micewith smaller changes in 1-month-old mice. Morphologic analysis of retina by light and electron microscopy showed no differences in retinal ultrastructure. Retinal function is mildly impaired in AQP4-null mice, suggesting a role for AQP4 in Muller cell fluid balance.The result supports the paradigm that AQP4 expression in supportive cells in the nervous system facilitates neural signal transduction in nearby electrically excitable cells.