Connexin gap junctions play an important role in hearing function, but the mechanism by which this contribution occurs is unknown. Connexins in the cochlea are expressed only in supporting cells; no connexin expression occurs in auditory sensory hair cells. A gap junctional channel is formed by two hemichannels. Here, we show that connexin hemichannels in the cochlea can release ATP at levels that account for the submicromolar concentrations measured in the cochlear fluids in vivo. The release could be increased 3-to 5-fold by a reduction of extracellular Ca 2؉ or an increase in membrane stress, and blocked by gap junctional blockers. We also demonstrated that extracellular ATP at submicromolar levels apparently affected outer hair cell (OHC) electromotility, which is an active cochlear amplifier determining cochlear sensitivity to sound stimulation in mammals. ATP reduced OHC electromotility and the slope factor of the voltage dependence and shifted the operating point to reduce the active amplifier gain. ATP also reduced the generation of distortion products. Immunofluorescent staining showed that purinergic receptors P2x2 and P2x7 were distributed on the OHC surface. Blockage of P2 receptors eliminated the effect of ATP on the OHC electromotility. The data revealed that there is a hemichannel-mediated, purinergic intercellular signaling pathway between supporting cells and hair cells in the cochlea to control hearing sensitivity. The data also demonstrated a potential source of ATP in the cochlea.active cochlear mechanics ͉ cochlear supporting cells ͉ connexin ͉ outer hair cell electromotility ͉ P2 receptor
Connexin26 (Cx26) and Cx30 are predominant isoforms of gap junction channels in the cochlea and play a critical role in hearing. In this study, the cellular distributions of Cx26 and Cx30 in the cochlear sensory epithelium of guinea pigs were examined by immunofluorescent staining and confocal microscopy in whole mounts of the cochlear sensory epithelium and dissociated cell preparations. The expression of Cx26 and Cx30 demonstrated a longitudinal gradient distribution in the epithelium and was reduced threefold from the cochlear apex to base. The reduction was more pronounced in the Deiters cells and pillar cells than in the Hensen cells. Cx26 was expressed in all types of supporting cells, but little Cx30 labeling was seen in the Hensen cells. Cx26 expression in the Hensen cells was concentrated mainly in the second and third rows, forming a distinct band along the sensory epithelium at its outer region. In the dissociated Deiters cells and pillar cells, Cx30 showed dense labeling at the cell bodies and processes in the reticular lamina. Cx26 labeling largely overlapped that of Cx30 in these regions. Cx26 and Cx30 were also coexpressed in the gap junctional plaques between Claudius cells. Neither Cx26 nor Cx30 labeling was seen in the hair cells and spiral ganglion neurons. These observations demonstrate that Cx26 and Cx30 have a longitudinal gradient distribution and distinct cellular expression in the auditory sensory epithelium. This further supports our previous reports that Cx26 and Cx30 can solely and concertedly perform different functions in the cochlea. Indexing termsgap junction; cochlear supporting cells; reticular lamina; spiral ganglion; inner ear; nonsyndromic hearing lossThe connexin gene family encodes gap junction channels in mammals. So far, more than 20 connexin genes and their corresponding isoforms have been identified . Each connexin shows tissue-or cell-specific expression, and most organs and tissues express more than one connexin (for reviews see Harris, 2001; Evans and Martin, 2002;Willecke et al., 2002). Connexin gap junctions perform electronic and metabolic communications between cells and play important roles in many aspects of cellular and physiological functions. In particular, gap junctions are known to play a critical role in hearing function. Connexin mutations can cause hearing loss and account for 70 -80% of nonsyndromic hearing loss in children (Kelsell et al., 1997;Denoyelle et al., 1997;Grifa et al., 1999 The mammalian cochlea is the auditory organ and contains sensory hair cells and nonsensory supporting cells. Gap junctional coupling is extensive in the cochlea (for reviews see Kikuchi et al., 2000;Zhao et al., 2006). In early histological studies, electron microscopy and dye injection demonstrated that intercellular communications existed in the organ of Corti (Jahnke, 1975;Gulley and Reese, 1976;Iurato et al., 1976Iurato et al., , 1977Hama and Saito, 1977;Santos-Sacchi and Dallos, 1983;Santos-Sacchi, 1987;Zwislocki et al., 1992). Kikuchi et al. (1995), using ...
Optogenetics has been developed to control the activities and functions of cells with high spatiotemporal resolution, cell‐type specificity, and flexibility. However, current optogenetic tools generally rely on visible light (e.g., blue or yellow) with shallow tissue penetration ability that does require invasive fiber‐optic probes to deliver visible light into organs and animal tissues. This often results in a series of side effects, such as tissue damage and unwanted inflammation. Fortunately, the emerging wireless optogenetic tools that can respond to deep‐tissue‐penetrating near‐infrared (NIR) light have attracted increasing attention due to their much‐reduced damage to living organisms. There are mainly two types of NIR‐activatable optogenetic tools: one uses lanthanide‐doped upconversion nanoparticles to transduce NIR light to visible light to modulate classical opsin‐expressing neurons; the other type couples with an NIR absorber to convert NIR light to heat to activate thermosensitive proteins. These NIR‐activatable optogenetic tools enable low‐invasive “remote control” activation and inhibition of cellular signaling pathways. This approach has great potential to help create more innovative therapies for diseases like cancer, diabetes, and neuronal disorders in the near future. Therefore, this review article summarizes the recent advances on design strategies and synthetic methods of NIR‐activatable nanomaterials for wireless optogenetic applications.
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