Regulator of G Protein Signalling 4 (RGS4) as a Novel Target for the Treatment of Sensorineural Hearing Loss

Abstract

We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the “post-exposure” treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6–8 weeks) were exposed to traumatic noise (110 dBSPL, 8–16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.

Status and trends of RGS16 based on data visualization analysis: A review

“…5, http://links.lww.com/MD/L407), each representing a subject category, and we obtained the subject categories clusters for the top 20 keywords. #0 CELL [21][22][23] in vitro, [24,25] mid-term around pathogenesis, [26,27] cancer, [28,29] Currently around inflammation, [28,30] injury, [31] antibody, [32,33] release, [34,35] protein signaling 16, [33,36] the latest is migration. [37,38] The most recently researched topic in the most researched discipline is corpus luteum.…”

Sensorineural hearing loss and cognitive impairment: three hypotheses

“…Adenosine is an endogenous purine nucleoside, and adenosine receptors, including A1R, A2R and A3R, are involved in the regulation of neurotransmitter release, oxidative stress responses, inflammation, blood flow, and a variety of intracellular signaling pathways including apoptosis. Activation of A1R protects inner ear hair cells, reduces hair cell death, and effectively protects against noise damage ( Kaur et al, 2016 ; Chang et al, 2017 ; Fok et al, 2020 ). Inhibition of A1R specifically was shown to cause cochlear nerve damage and to increase susceptibility to HL ( Vlajkovic et al, 2017 ).…”

Purinergic Signalling in the Cochlea

“…Previous studies have shown that the “post-exposure” treatment with adenosine A 1 R agonists confers partial protection against acoustic trauma and other forms of SNHL [ 87 , 88 ]. Another study attempted to rescue noise-induced cochlear injury by post-exposure treatment targeting A 1 R without using receptor agonists [ 100 ]. This was achieved by pharmacological inhibition of the protein that regulates G protein signalling by the A 1 R (Regulator of G protein Signalling 4, RGS4).…”

“…Functional improvement was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. RGS inhibitors thus represent a novel paradigm for treating noise-induced cochlear injury and possibly other forms of SNHL [ 100 ].…”