In vitro pharmacologic characterization of a cholinergic receptor on outer hair cells

Eróstegui, Carlos; Norris, Charles H.; Bobbin, Richard P.

doi:10.1016/0378-5955(94)90182-1

Cited by 115 publications

(88 citation statements)

References 39 publications

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“…Drugs perfused into the perilymph compartment of scala tympani have ready access to the hair cells and the synaptic regions of hair cells, a view supported by investigations in which various stains demonstrated ready access to structures within the organ of Corti when introduced via the scala tympani perilymph compartment (e.g., [21]). Additionally, a comparison of the concentrations of cholinergic antagonists required to block the cochlear efferents in vivo [41,42] to those effective at in vitro isolated outer hair cells [44] shows remarkably close agreement.…”

Section: Comparison To Other Delivery Methodsmentioning

confidence: 73%

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: 73%

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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“…The striking similarities found so far between the pharmacology of recombinant nAChRs assembled from a9 and a10 subunits (Elgoyhen et al 1994(Elgoyhen et al , 2001) and that of native nAChRs present in isolated OHCs from different species (Housley and Ashmore 1991; Fuchs and Murrow 1992;Kakehata et al 1993;Erostegui et al 1994;Blanchet et al 1996;Chen et al 1996;Dulon and Lenoir 1996;Evans 1996;McNiven et al 1996) suggest that the native cholinergic hair cell receptor is assembled from both a9 and a10 subunits. Moreover, this notion is further reinforced by in situ hybridization studies carried out in rat cochlear OHCs and IHCs at the same postnatal ages as those employed in the present study (Elgoyhen et al 2001;FIG.…”

Section: Discussionmentioning

confidence: 91%

“…The cholinergic hair cell receptor displays an unusual pharmacological profile which does not resemble the one described for muscle or neuronal nAChRs (Housley and Ashmore 1991; Fuchs and Murrow 1992;Kakehata et al 1993;Erostegui et al 1994;Blanchet et al 1996;Chen et al 1996;Dulon and Lenoir 1996;Evans 1996;McNiven et al 1996), thus suggesting the presence of a new receptor subtype (Fuchs 1996). The more recently cloned a9 and a10 gene subunits are distant members of the nAChR family and, when expressed in Xenopus laevis oocytes, form a heteromeric receptor-channel complex that displays a pharmacological profile distinctly different from that of other cholinergic receptors, with sensitivity to glycinergic, gabaergic, serotonergic, as well as nicotinic and muscarinic antagonists (Elgoyhen et al 1994(Elgoyhen et al , 2001).…”

Section: Introductionmentioning

confidence: 99%

Linopirdine Blocks α9α10-Containing Nicotinic Cholinergic Receptors of Cochlear Hair Cells

Gómez-Casati

Katz

Glowatzki

et al. 2004

JARO

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Studies of the electrophysiological response to acetylcholine (ACh) in mammalian outer hair cells (OHCs) are hindered by the presence of a large potassium current, I K,n , most likely mediated by channels containing the KCNQ4 subunit. Since I K,n can be blocked by linopirdine, cholinergic effects might be better revealed in the presence of this compound. The aim of the present work was to study the effects of linopirdine on the ACh-evoked responses through a9a10-containing native and recombinant nicotinic cholinergic receptors. Responses to ACh were blocked by linopirdine in both OHCs and inner hair cells (IHCs) of rats at postnatal days 21-27 (OHCs) and 9-11 (IHCs). In addition, linopirdine blocked responses of recombinant a9a10 nicotinic cholinergic receptors (nAChRs) in a concentrationdependent manner with an IC 50 of 5.2 lM. Block by linopirdine was readily reversible, voltage independent, and surmountable at high concentrations of ACh, thus suggestive of a competitive type of interaction with the receptor. The present results contribute to the pharmacological characterization of a9a10-containing nicotinic receptors and indicate that linopirdine should be used with caution when analyzing the cholinergic sensitivity of cochlear hair cells.

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“…␣9␣10 nAChRs in Native Hair Cells: Functional Implications. The signature pharmacology of the nAChR at the efferent olivocochlear hair cell synapse (7,21,22) was sufficiently distinct that before the cloning and characterization of the ␣9 nAChR subunit, none of the extant recombinant nAChRs were likely candidates to fill the role. Since then, however, characterization of recombinant ␣9 nAChRs (14-16) and generation of a transgenic ␣9 Ϫ/Ϫ null mutant mouse (23) has provided a combination of data compelling enough to propose a central role for ␣9-containing nAChRs in the cholinergic biology of mechanosensory hair cells.…”

Section: Discussionmentioning

confidence: 99%

α10: A determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells

Elgoyhen

Vetter

Katz

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

633

795

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We report the cloning and characterization of rat ␣10, a previously unidentified member of the nicotinic acetylcholine receptor (nAChR) subunit gene family. The protein encoded by the ␣10 nAChR subunit gene is most similar to the rat ␣9 nAChR, and both ␣9 and ␣10 subunit genes are transcribed in adult rat mechanosensory hair cells. Injection of Xenopus laevis oocytes with ␣10 cRNA alone or in pairwise combinations with either ␣2-␣6 or ␤2-␤4 subunit cRNAs yielded no detectable ACh-gated currents. However, coinjection of ␣9 and ␣10 cRNAs resulted in the appearance of an unusual nAChR subtype. Compared with homomeric ␣9 channels, the ␣9␣10 nAChR subtype displays faster and more extensive agonist-mediated desensitization, a distinct currentvoltage relationship, and a biphasic response to changes in extracellular Ca 2؉ ions. The pharmacological profiles of homomeric ␣9 and heteromeric ␣9␣10 nAChRs are essentially indistinguishable and closely resemble those reported for endogenous cholinergic eceptors found in vertebrate hair cells. Our data suggest that efferent modulation of hair cell function occurs, at least in part, through heteromeric nAChRs assembled from both ␣9 and ␣10 subunits.

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In vitro pharmacologic characterization of a cholinergic receptor on outer hair cells

Cited by 115 publications

References 39 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

Linopirdine Blocks α9α10-Containing Nicotinic Cholinergic Receptors of Cochlear Hair Cells

α10: A determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells

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