Effects of Adenosine 5′-triphosphate and related agonists on cochlear function

Kujawa, Sharon G.; Eróstegui, Carlos; Fallon, Maureen; Crist, Jennifer R.; Bobbin, Richard P.

doi:10.1016/0378-5955(94)90091-4

Cited by 80 publications

(50 citation statements)

References 31 publications

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“…The practice of placing drugs of interest within cochlear perilymphatic spaces via a perfusion technique is a method with a long history of successful application (e.g., [32][33][34][35][36][37][38][39][40][41][42]). When carefully administered, the technique itself has been shown to have little effect on a variety of gross cochlear and neural potentials as recorded from sites within and near the cochlea (e.g., [43]).…”

Section: Comparison To Other Delivery Methodsmentioning

confidence: 99%

“…Most methods of perfusion of the guinea pig scala tympani are derivations of Konishi's technique, in which an inlet hole is placed in the scala tympani and an exit hole is placed either in the apex of the cochlea or in the scala vestibuli (e.g., [32][33][34][35][36][37][38][39][40][41][42]). This allows reasonable control of drug concentration and agents can be distributed throughout the length of the cochlea.…”

Section: Comparison To Other Delivery Methodsmentioning

confidence: 99%

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Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

Chen

Kujawa

McKenna

et al. 2005

Journal of Controlled Release

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Rapid progress in understanding the molecular mechanisms associated with cochlear and auditory nerve degenerative processes offers hope for the development of gene-transfer and molecular approaches to treat these diseases in patients. For therapies based on these discoveries to become clinically useful, it will be necessary to develop safe and reliable mechanisms for the delivery of drugs into the inner ear, bypassing the blood-labyrinthine barrier. Toward the goal of developing an inner ear perfusion device for human use, a reciprocating microfluidic system that allows perfusion of drugs into the cochlear perilymph through a single inlet hole in scala tympani of the basal turn was developed. The performance of a prototype, extracorporeal reciprocating perfusion system in guinea pigs is described. Analysis of the cochlear distribution of compounds after perfusion took advantage of the place-dependent generation of responses to tones along the length of the cochlea. Perfusion with a control artificial perilymph solution had no effect. Two drugs with wellcharacterized effects on cochlear physiology, salicylate (5 mM) and DNQX (6,7-Dinitroquinoxaline-2,3-dione; 100 and 300 μM), reversibly altered responses. The magnitude of drug effect decreased with distance from the perfusion pipette for up to 10 mm, and increased with dose and length of application.

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Section: Comparison To Other Delivery Methodsmentioning

confidence: 99%

Section: Comparison To Other Delivery Methodsmentioning

confidence: 99%

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

Chen

Kujawa

McKenna

et al. 2005

Journal of Controlled Release

Self Cite

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“…It has been found that intracochlear perfusion of ATP could reduce both the endocochlear potential (EP) and CM [3]. The intracochlear perfusion of ATP also decreased DPOAEs [2,3]. These proposed changes resulted from shifting the operating point of the cochlear amplifier to reduce the amplifier gain [31].…”

Section: Possible Mechanisms Of Atp Regulation In Hearing Functionmentioning

confidence: 99%

“…An early experiment demonstrated that the application of ATP to the perilymph in the guinea pig cochlea affected auditory nerve activity [1]. Intracochlear perfusion of ATP also reduced the cochlear microphonics (CM) and the compound action potential [2][3][4][5]. It has been reported that ATP can evoke inward currents and raise the intracellular Ca ++ concentration in cochlear outer and inner hair cells, thereby modifying sound transduction and neurotransmission [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that ATP can evoke inward currents and raise the intracellular Ca ++ concentration in cochlear outer and inner hair cells, thereby modifying sound transduction and neurotransmission [6][7][8][9][10][11]. ATP can also reduce the cubic component (2f 1 − f 2 ) in distortion product otoacoustic emissions (DPOAEs) [2,12], which is generated by active cochlear mechanics.…”

Section: Introductionmentioning

confidence: 99%

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ATP activates P2x receptors and requires extracellular Ca++ participation to modify outer hair cell nonlinear capacitance

Zhao

2008

Pflugers Arch - Eur J Physiol

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Intracochlear ATP is an important mediator in regulating hearing function. ATP can activate ionotropic purinergic (P2x) and metabotropic purinergic (P2y) receptors to influence cell functions. In this paper, we report that ATP can activate P2x receptors directly to modify outer hair cell (OHC) electromotility, which is an active cochlear amplifier determining hearing sensitivity and frequency selectivity in mammals. We found that ATP, but not UTP, a P2y receptor agonist, reduced the OHC electromotility-associated nonlinear capacitance (NLC) and shifted its voltage dependence to the right (depolarizing) direction. Blockage of the activation of P2x receptors by pyridox-alphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), suramin, and 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) could block the ATP effect. This modification also required extracellular Ca ++ participation. Removal of extracellular Ca ++ abolished the ATP effect. However, chelation of intracellular Ca ++ concentration by a fast calciumchelating reagent 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA, 10 mM) did not affect the effect of ATP on NLC. The effect is also independent of K + ions. Substitution of Cs + for intracellular or extracellular K + did not affect the ATP effect. Our findings indicate that ATP activates P2x receptors instead of P2y receptors to modify OHC electromotility. Extracellular Ca ++ is required for this modification.

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Immunohistochemical localization of adenosine 5`-triphosphate-gated ion channel P2X2 receptor subunits in adult and developing rat cochlea

2000

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Substantial in vitro and in vivo data support a role for extracellular adenosine 5`‐triphosphate (ATP) and associated P2 receptors in cochlear function. However, the precise spatiotemporal distribution of the involved receptor protein(s) has not been determined. By using a specific antiserum and immunoperoxidase labeling, the tissue distribution of the P2X2 subunit of the ATP‐gated ion channel was investigated. Here, we describe the first extensive immunohistochemical mapping of P2X2 receptor subunits in the adult and developing rat cochlea. In the adult, immunoreactivity was observed in most cells bordering on the endolymphatic compartment (scala media), particularly in the supporting cells. Hair cells were not immunostained by the P2X2 antiserum, except for outer hair cell stereocilia. In addition, weak immunolabeling was observed in some spiral ganglion neurons. P2X2 receptor subunit protein expression during labyrinthine ontogeny was detected first on embryonic day 19 in the spiral ganglion and in associated nerve fibers extending to the inner hair cells. Immunostaining also was observed underneath outer hair cells, and, by postnatal day 6 (P6), intense immunolabeling was seen in the synaptic regions of both types of hair cell. Supporting cells of the sensory epithelium were labeled at P0. This labeling became most prominent from the onset of cochlear function (P8–P12). Conversely, expression in the vascular stria declined from this time. By P21, the pattern of immunolabeling was similar to that found in the adult. The localization and timing of P2X2 immunoreactivity suggest involvement of extracellular ATP and associated ATP‐gated ion channels in important physiological events, such as inner ear ontogeny, sound transduction, cochlear micromechanics, electrochemical homeostasis, and auditory neurotransmission. J. Comp. Neurol. 421:289–301, 2000. © 2000 Wiley‐Liss, Inc.

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Effects of Adenosine 5′-triphosphate and related agonists on cochlear function

Cited by 80 publications

References 31 publications

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

ATP activates P2x receptors and requires extracellular Ca++ participation to modify outer hair cell nonlinear capacitance

Immunohistochemical localization of adenosine 5`-triphosphate-gated ion channel P2X2 receptor subunits in adult and developing rat cochlea

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