cGMP survival signalling for prevention of hearing loss

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The potential capacity of cGMP activation for protection of sensory organs in the inner ear is not fully understood. Our previous findings suggested that the phosphodiesterase 5 inhibitor may provide protection against trauma-induced hearing loss and sensory hair cell death potentially by signalling via a common cGMP/cGMP-dependent protein kinase type I (cGKI) pathway in the inner ear. At the same time we have identified a higher vulnerability and a reduced recovery from noise-induced auditory injury in mouse mutants globally lacking cGKI. It is the overall aim of this project to elucidate the role of the cGMP generators and effectors involved in hair cell survival in the injured or challenged auditory system, and to monitor spatiotemporal cGMP dynamics during both sudden and progressive damage. In order to validate this pathway for early identification and treatment of hearing loss, we will monitor the auditory responses in the presence and absence of various cGMP elevating agents in different animal models. We have subjected membrane-bound guanylyl cyclase (GC-A/B) mutants and mice lacking subunits of the soluble NO-GC to a combination of physiological and molecular tests for spontaneous or induced auditory signal processing disorders. We found that GC-A mediates protection from noise-induced hearing loss, whereas NO-GC may have autonomous functions in inner and outer hair cells including changes in central brainstem adaptation and distinct efferent feedback control. Further studies need to dissect the individual functions of the NO-GC isoforms in sensory cells and central nuclei for spontaneous and trauma-induced hearing loss and their potential use as pharmacological targets in the development of auditory pathologies. We will further explore the molecular and cellular aspects of degeneration and regeneration during auditory injury, which should validate the therapeutic potential of GC-A and its ligands for the protection of the ear during auditory stress. GC-B deletion leads to failure of auditory nerve bifurcation in the auditory brainstem. We suggest that this may lead to a moderate hearing loss possibly linked to disturbed efferent feedback loops. Therefore also the role of GC-B/cGMP for the central inhibitory neuronal circuits in the cochlear nucleus complex and for damage-induced changes in binaural hearing, adaptation, and plasticity will be explored in detail. The functional experiments shall be corroborated by exploring the cGMP effector proteins downstream of the distinct cGMP generators and by directly visualizing cGMP in different cell types of the organ of corti under pathophysiological conditions using transgenic mice with inducible expression of a cGMP sensor specifically in different auditory cell types. Using comprehensive cellular, functional and perceptual assays we may decode the cGMP cascade in the ear and contribute to the general state of knowledge for cell protection and survival by cGMP and cGMP elevating compounds.