Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell Survival
Purinergic signaling regulates important physiological processes and the homeostatic response to stress in the cochlea via extracellular nucleosides (adenosine) and nucleotides (ATP, UTP). Using a previously established organotypic culture model, the current study investigated the effect of purinerg...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2019.00207/full |
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| author | Shelly C. Y. Lin Peter R. Thorne Gary D. Housley Srdjan M. Vlajkovic |
| author_facet | Shelly C. Y. Lin Peter R. Thorne Gary D. Housley Srdjan M. Vlajkovic |
| author_sort | Shelly C. Y. Lin |
| collection | DOAJ |
| description | Purinergic signaling regulates important physiological processes and the homeostatic response to stress in the cochlea via extracellular nucleosides (adenosine) and nucleotides (ATP, UTP). Using a previously established organotypic culture model, the current study investigated the effect of purinergic P1 (adenosine) and P2 (ATP) receptor activation on the survival of the sensory hair cell population in the cochlea exposed to the ototoxic aminoglycoside neomycin. Organ of Corti explants were obtained from C57BL/6 mice at postnatal day 3 (P3) and maintained in normal culture medium (with or without purine receptor agonists or analogs) for 19.5 h prior to neomycin exposure (1 mM, 3 h) followed by a further incubation for 19.5 h in culture medium. The cochlear explants were then fixed in 4% paraformaldehyde (PFA) and sensory hair cells labeled with Alexa 488-phalloidin. Neomycin induced a substantial loss of the sensory hair cells, mostly in the middle segment of the cochlea. This neomycin-induced ototoxicity was unaffected by the addition of P2 receptor agonists (ATP and UTP) in the culture medium, whilst the addition of their slowly-hydrolyzable analogs (ATPγS, UTPγS) aggravated neomycin-induced sensory hair cell loss. In contrast, the activation of P1 receptors by adenosine or adenosine amine congener (ADAC) conferred partial protection from neomycin ototoxicity. This study demonstrates a pro-survival effect of P1 receptor stimulation, whilst prolonged activation of P2 receptors has an opposite effect. Based on these findings, we postulate that P1 and P2 receptors orchestrate differential responses to cochlear injury and that the balance of these receptors is important for maintaining cochlear homeostasis following ototoxic injury. |
| first_indexed | 2024-12-11T19:49:23Z |
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| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-11T19:49:23Z |
| publishDate | 2019-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-69bf98ca2ba7465f97ea3ca811aa878b2022-12-22T00:52:48ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022019-05-011310.3389/fncel.2019.00207439090Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell SurvivalShelly C. Y. Lin0Peter R. Thorne1Gary D. Housley2Srdjan M. Vlajkovic3Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New ZealandDepartment of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New ZealandDepartment of Physiology and Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, Sydney, NSW, AustraliaDepartment of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New ZealandPurinergic signaling regulates important physiological processes and the homeostatic response to stress in the cochlea via extracellular nucleosides (adenosine) and nucleotides (ATP, UTP). Using a previously established organotypic culture model, the current study investigated the effect of purinergic P1 (adenosine) and P2 (ATP) receptor activation on the survival of the sensory hair cell population in the cochlea exposed to the ototoxic aminoglycoside neomycin. Organ of Corti explants were obtained from C57BL/6 mice at postnatal day 3 (P3) and maintained in normal culture medium (with or without purine receptor agonists or analogs) for 19.5 h prior to neomycin exposure (1 mM, 3 h) followed by a further incubation for 19.5 h in culture medium. The cochlear explants were then fixed in 4% paraformaldehyde (PFA) and sensory hair cells labeled with Alexa 488-phalloidin. Neomycin induced a substantial loss of the sensory hair cells, mostly in the middle segment of the cochlea. This neomycin-induced ototoxicity was unaffected by the addition of P2 receptor agonists (ATP and UTP) in the culture medium, whilst the addition of their slowly-hydrolyzable analogs (ATPγS, UTPγS) aggravated neomycin-induced sensory hair cell loss. In contrast, the activation of P1 receptors by adenosine or adenosine amine congener (ADAC) conferred partial protection from neomycin ototoxicity. This study demonstrates a pro-survival effect of P1 receptor stimulation, whilst prolonged activation of P2 receptors has an opposite effect. Based on these findings, we postulate that P1 and P2 receptors orchestrate differential responses to cochlear injury and that the balance of these receptors is important for maintaining cochlear homeostasis following ototoxic injury.https://www.frontiersin.org/article/10.3389/fncel.2019.00207/fullaminoglycoside ototoxicitycochlear explantsensory hair cellsadenosineATPP1 receptor |
| spellingShingle | Shelly C. Y. Lin Peter R. Thorne Gary D. Housley Srdjan M. Vlajkovic Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell Survival Frontiers in Cellular Neuroscience aminoglycoside ototoxicity cochlear explant sensory hair cells adenosine ATP P1 receptor |
| title | Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell Survival |
| title_full | Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell Survival |
| title_fullStr | Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell Survival |
| title_full_unstemmed | Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell Survival |
| title_short | Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell Survival |
| title_sort | purinergic signaling and aminoglycoside ototoxicity the opposing roles of p1 adenosine and p2 atp receptors on cochlear hair cell survival |
| topic | aminoglycoside ototoxicity cochlear explant sensory hair cells adenosine ATP P1 receptor |
| url | https://www.frontiersin.org/article/10.3389/fncel.2019.00207/full |
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