Adenosine A2B receptor: A pathogenic factor and a therapeutic target for sensorineural hearing loss

Manalo, Jeanne; Liu, Hong; Ding, Dalian; Hicks, John; Sun, Hong; Salvi, Richard; Kellems, Rodney E.; Pereira, Fred A.; Xia, Yang

doi:10.1096/fj.202000939r

Cited by 10 publications

(10 citation statements)

References 64 publications

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“…Data about an inhibitory role of A 2 B R in myelin formation are consistent with recent findings from Manalo et al (2020) who demonstrated that elevated cochlear adenosine levels in ADA –/– mice is associated with sensorineural hearing loss (SNHL) due to cochlear nerve fiber demyelination and mild hair cell loss. Intriguingly, A 2 B R-specific antagonists administered in ADA –/– mice significantly restored auditory capacity, nerve fiber density and myelin compaction.…”

Section: Introductionsupporting

confidence: 88%

A2B Adenosine Receptors and Sphingosine 1-Phosphate Signaling Cross-Talk in Oligodendrogliogenesis

et al. 2021

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Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain. Impairments in the process of myelination, or demyelinating insults, might cause chronic diseases such as multiple sclerosis (MS). Under physiological conditions, remyelination is an ongoing process throughout adult life consisting in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs). During pathological events, this process fails due to unfavorable environment. Adenosine and sphingosine kinase/sphingosine 1-phosphate signaling axes (SphK/S1P) play important roles in remyelination processes. Remarkably, fingolimod (FTY720), a sphingosine analog recently approved for MS treatment, plays important roles in OPC maturation. We recently demonstrated that the selective stimulation of A2B adenosine receptors (A2BRs) inhibit OPC differentiation in vitro and reduce voltage-dependent outward K+ currents (IK) necessary to OPC maturation, whereas specific SphK1 or SphK2 inhibition exerts the opposite effect. During OPC differentiation A2BR expression increases, this effect being prevented by SphK1/2 blockade. Furthermore, selective silencing of A2BR in OPC cultures prompts maturation and, intriguingly, enhances the expression of S1P lyase, the enzyme responsible for irreversible S1P catabolism. Finally, the existence of an interplay between SphK1/S1P pathway and A2BRs in OPCs was confirmed since acute stimulation of A2BRs activates SphK1 by increasing its phosphorylation. Here the role of A2BR and SphK/S1P signaling during oligodendrogenesis is reviewed in detail, with the purpose to shed new light on the interaction between A2BRs and S1P signaling, as eventual innovative targets for the treatment of demyelinating disorders.

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Section: Introductionsupporting

confidence: 88%

A2B Adenosine Receptors and Sphingosine 1-Phosphate Signaling Cross-Talk in Oligodendrogliogenesis

et al. 2021

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“…Interestingly, it has been recently reported that when the enzyme replacement therapy with PEG-ADA is performed early, it is effective in improving hearing defects in Ada−/− mice (Xu et al, 2019). ADA enzyme therapy in these mice normalized cochlear adenosine levels, and prevented demyelination while treatment with an A2BR-antagonist improved hearing loss and myelin compaction (Manalo et al, 2020).…”

Section: Adenosine Deaminasementioning

confidence: 99%

Metabolic Aspects of Adenosine Functions in the Brain

et al. 2021

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Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5′-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington’s disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.

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“…The distribution of four adenosine receptors in the cochlea is diverse ( Vlajkovic et al, 2009 ; Manalo et al, 2020 ). AA1R is distributed in SGNs, and in SCs and IHCs of the OC, but AA2AR and AA2BR localize to SGNs, OC, and cochlear vessels.…”

Section: Roles Of Class a G Protein-coupled Receptors In Cochleamentioning

confidence: 99%

“…Administration of AA1R probiotics R-PIA and ADAC was more significant in inhibiting cisplatin-induced ototoxicity ( Vlajkovic et al, 2010 ; Kaur et al, 2016 ), and the protective effect of R-PIA was inhibited by combined use of AA1R antagonist DPCPX ( Whitworth et al, 2004 ). In contrast, AA2AR and AA2BR play a negative regulatory role in hearing loss, with cochlear protection achieved by the use of the inhibitor (istradefylline) ( Han et al, 2019 ; Manalo et al, 2020 ; Shin et al, 2021 ).…”

Section: Roles Of Class a G Protein-coupled Receptors In Cochleamentioning

confidence: 99%

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

Guo²,

Fu³

et al. 2022

Front. Mol. Neurosci.

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The prevalence of hearing loss-related diseases caused by different factors is increasing worldwide year by year. Currently, however, the patient’s hearing loss has not been effectively improved. Therefore, there is an urgent need to adopt new treatment measures and treatment techniques to help improve the therapeutic effect of hearing loss. G protein-coupled receptors (GPCRs), as crucial cell surface receptors, can widely participate in different physiological and pathological processes, particularly play an essential role in many disease occurrences and be served as promising therapeutic targets. However, no specific drugs on the market have been found to target the GPCRs of the cochlea. Interestingly, many recent studies have demonstrated that GPCRs can participate in various pathogenic process related to hearing loss in the cochlea including heredity, noise, ototoxic drugs, cochlear structure, and so on. In this review, we comprehensively summarize the functions of 53 GPCRs known in the cochlea and their relationships with hearing loss, and highlight the recent advances of new techniques used in cochlear study including cryo-EM, AI, GPCR drug screening, gene therapy vectors, and CRISPR editing technology, as well as discuss in depth the future direction of novel GPCR-based drug development and gene therapy for cochlear hearing loss. Collectively, this review is to facilitate basic and (pre-) clinical research in this area, and provide beneficial help for emerging GPCR-based cochlear therapies.

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Adenosine A2B receptor: A pathogenic factor and a therapeutic target for sensorineural hearing loss

Cited by 10 publications

References 64 publications

A2B Adenosine Receptors and Sphingosine 1-Phosphate Signaling Cross-Talk in Oligodendrogliogenesis

A2B Adenosine Receptors and Sphingosine 1-Phosphate Signaling Cross-Talk in Oligodendrogliogenesis

Metabolic Aspects of Adenosine Functions in the Brain

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

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