Genetics of guanylyl cyclase pathways in the cochlea and their influence on hearing

Abstract

Although hearing loss is the most common sensory deficit in Western societies, there are no successful pharmacological treatments for this disorder. Recent experiments have demonstrated that manipulation of intracellular cyclic guanosine monophosphate (cGMP) concentrations can have both beneficial and harmful effects on hearing. In this review, we will examine the role of cGMP as a key second messenger involved in many aspects of cochlear function and discuss the known functions of downstream effectors of cGMP in sound processing. The nitric oxide-stimulated soluble guanylyl cyclase system (sGC) and the two natriuretic peptide-stimulated particulate GCs (pGCs) will be more extensively covered because they have been studied most thoroughly. The cochlear GC systems are attractive targets for medical interventions that improve hearing while simultaneously representing an under investigated source of sensorineural hearing loss.

Guanylyl Cyclase A/cGMP Signaling Slows Hidden, Age- and Acoustic Trauma-Induced Hearing Loss

“…Using isolated hair cells and SG of the mature cochlea, we identified the NPs ANP and BNP as well as GC-A in OHCs and SG and confirmed the presence of NPs in IHCs, corroborating previous studies (Meyer zum Gottesberge et al, 1991;Yoon and Anniko, 1994;Suzuki et al, 1998Suzuki et al, , 2000Kuhn, 2003Kuhn, , 2009Schulz, 2005;Kemp-Harper and Feil, 2008;Kleppisch and Feil, 2009;Alexander et al, 2011;Qiao et al, 2011;Sun et al, 2013Sun et al, , 2014Shen et al, 2015;Möhrle et al, 2017;Fitzakerley and Trachte, 2018). We could not detect GC-A in IHCs.…”

“…Based on these results, future studies should focus on the potential of enhancing ANP/GC-A/cGMP signaling for restoration of normal hearing to counteract hidden hearing loss and IHC synaptopathy, as well as age-related hearing loss or NIHL. Here, efforts to stimulate GC-A through the ligand ANP may be particularly promising because (i) ANP levels in endolymph are two orders of magnitude higher than in plasma (Yoon et al, 2012); (ii) the ANP-producing serine protease corin is expressed in the cochlea, indicating that cochlear cells are capable of converting proANP to ANP (Labine et al, 2015;Fitzakerley and Trachte, 2018); and (iii) preliminary studies pointed to a transient improvement in hearing thresholds following systemic ANP administration (Yoon et al, 2015).…”

“…Peripheral age-dependent hearing loss has recently been defined as a severe but amendable risk factor for the development of dementia. Thus, treatment of hearing deficits can be important for cognitive health 1 (Livingston and Frankish, 2015;Fitzakerley and Trachte, 2018).…”

“…There is evidence that the genetics and function of cochlear cyclic guanosine monophosphate (cGMP)-forming guanylyl cyclases (GCs) play a fundamental role in normal hearing and cochlear pathophysiology (Fitzakerley and Trachte, 2018). A protective role of the cGMP-dependent protein kinase I (cGKI) signaling cascade for IHC synapses and OHCs was shown in rodent models of noise-induced damage (Jaumann et al, 2012).…”

Atrial Natriuretic Peptide Promotes Neurite Outgrowth and Survival of Cochlear Spiral Ganglion Neurons in vitro Through NPR-A/cGMP/PKG Signaling

“…Through binding to its specific receptors on the cell surface, NPR-A (also known as NPR1 or GC-A) and NPR-C, ANP exerts a fundamental role in the modulation of cardiovascular homeostasis ( Potter et al, 2009 ). ANP, brain NP (BNP), and C-type NP (CNP) are structurally related peptides belonging to members of the NP family that are widely distributed in the mammalian central nervous system (CNS) ( Cao and Yang, 2008 ; Mahinrad et al, 2016 ), especially in peripheral sensory organs such as the dorsal root, trigeminal, retinal, and cochlear ganglia ( Lamprecht and Meyer zum Gottesberge, 1988 ; Furuta et al, 1995 ; Abdelalim and Tooyama, 2010 ; Xu et al, 2010 ; Loo et al, 2012 ; Abdelalim et al, 2013 ; Vilotti et al, 2013 ; Fitzakerley and Trachte, 2018 ). Recent research has shown the involvement of the BNP/NPR-A signaling pathway in the modulation of nociceptive processing for pain ( Zhang et al, 2010 ) and itch responses ( Solinski et al, 2019 ).…”