The role of cGMP signalling in auditory processing in health and disease

Abstract

cGMP is generated by the cGMP-forming guanylyl cyclases (GCs), the intracellular nitric oxide (NO)-sensitive (soluble) guanylyl cyclase (sGC) and transmembrane GC (e.g. GC-A and GC-B). In summarizing the particular role of cGMP signalling for hearing, we show that GC generally do not interfere significantly with basic hearing function but rather sustain a healthy state for proper temporal coding, fast discrimination and adjustments during injury. sGC is critical for the integrity of the first synapse in the ascending auditory pathway, the inner hair cell synapse. GC-A promotes hair cell stability under stressful conditions such as acoustic trauma or ageing. GC-B plays a role in the development of efferent feed-back and gain control.Regarding the crucial role hearing has for language development, speech discrimination and cognitive brain functions, differential pharmaceutical targeting of GCs offers therapeutic promise for the restoration of hearing. K E Y W O R D S central auditory processing, guanylyl cyclases, hearing function, temporal coding | INTRODUCTIONWorldwide, hearing loss is considered to be the fourth leading cause of disability, which today, in industrialized countries, affects about 190 million people. The rising number of affected people in the younger population and the dramatic shift in societal demographics, will soon significantly increase the total number of people with hearing deficits. While hearing loss is not life-threatening, mid-age hearing disorder was recently shown to be a major risk factor for dementia (Livingston et al., 2017). Indeed, the prevention of hearing loss with age has been suggested as a major action on lowering the future prevalence of dementia (Montero-Odasso et al., 2020). While to date degeneration of the stria vascularis and its vasculature were considered to be a main cause of hearing loss with age (Fischer et al., 2020;Frisina & Frisina, 2013), previous studies suggested that damage to outer hair cells proceeds stria degeneration (Wu et al., 2019). Outer hair cells are electromotile and serve as a piezo-like motor in the inner ear to amplify the vibrations of the basilar membrane in the cochlea (Dallos & Harris, 1978). Gradual noise damage to outer hair cells over lifetime was labelled as a major contributor to hearing loss in humans (Wu et al., 2019).

Loss of central mineralocorticoid or glucocorticoid receptors impacts auditory nerve processing in the cochlea

“…Vasopressin and oxytocin are expressed not only in the limbic forebrain (Cilz et al, 2019) but also in the cochlea (Reuss et al, 2009). Oxytocin also stimulates soluble guanylate cyclase and increases intracellular cGMP (Porzionato et al, 2010;Conrad et al, 1993), the signaling cascade that was shown to act on auditory nerve processing (Chumak et al, 2016;Marchetta et al, 2020Marchetta et al, , 2021.…”

C-type natriuretic peptide preserves central neurological function by maintaining blood-brain barrier integrity

“…A central role for CNP has been established in relation to its NPR-B/cGMP-mediated promotion of axonal bifurcation in somatosensory neurons and auditory function ( Dumoulin et al, 2021 ; Marchetta et al, 2022 ). However, a wider contribution of the peptide to the physiological regulation of cognition, motor function and BBB integrity has not been fully elucidated, despite previous work hinting at a role for CNP in these settings ( Vigne and Frelin, 1992 ; Pedram et al, 2002 ; Barmashenko et al, 2014 ; Rapley et al, 2018 ).…”

Proton Mechanisms of Neurotransmission and Calcium Signalling for Impulse Initiation, Development and Propagation

“…In the eye, the activation of GPCRs via the PLC/IP3 pathway occurs by means of the cells containing melanopsin, such as the ganglion cells of the iris, whilst the cells of the retina containing rhodopsin and the cells of the auricular cochlea follow a different pathway, via PDE/cGMP [112,113]. In this case, the protons are generated by the hydrolysis of cGMP and the dissociation of acid glutamate, as described below in paragraph 2.…”