Ryanodine is a positive modulator of acetylcholine receptor gating in cochlear hair cells

Javier Zorrilla De San Martín, Jimena Ballestero, Eleonora Katz, A. Belén Elgoyhen, Paul Albert Fuchs

Research output: Contribution to journalArticle

Abstract

The efferent synaptic specialization of hair cells includes a near-membrane synaptic cistern, whose presence suggests a role for internal calcium stores in cholinergic inhibition. Calcium release channels from internal stores include 'ryanodine receptors', whose participation is usually demonstrated by sensitivity to the eponymous plant alkaloid, ryanodine. However, use of this and other store-active compounds on hair cells could be confounded by the unusual pharmacology of the α9α10-containing hair cell nicotinic cholinergic receptor (nAChR), which has been shown to be antagonized by a broad spectrum of compounds. Surprisingly, we found that ryanodine, rather than antagonizing, is a positive modulator of the α9α10 nAChR expressed in Xenopus oocytes, the first such compound to be found. The effect of ryanodine was to increase the apparent affinity and efficacy for acetylcholine (ACh). Correspondingly, ACh-evoked currents through the isolated cholinergic receptors of inner hair cells in excised mouse cochleas were approximately doubled by 200 μM ryanodine, a concentration that inhibits gating of the ryanodine receptor itself. This unusual positive modulation was not unique to the mammalian receptor. The response to ACh of chicken 'short' hair cells likewise was enhanced in the presence of 100 μM ryanodine. This facilitatory effect on current through the AChR could enhance brief (∼1 s) activation of associated calcium-dependent K+ (SK) channels in both chicken short hair cells and rat outer hair cells. This novel effect of ryanodine provides new opportunities for the design of compounds that potentiate α9α10- mediated responses and for potential inner ear therapeutics based on this interaction.

Original languageEnglish (US)
Pages (from-to)474-483
Number of pages10
JournalJARO - Journal of the Association for Research in Otolaryngology
Volume8
Issue number4
DOIs
StatePublished - Dec 2007

Fingerprint

Auditory Hair Cells
Ryanodine
Cholinergic Receptors
Acetylcholine
Ryanodine Receptor Calcium Release Channel
Outer Auditory Hair Cells
Inner Auditory Hair Cells
Chickens
Calcium
Synaptic Membranes
Cochlea
Nicotinic Receptors
Inner Ear
Calcium Channels
Xenopus
Alkaloids
Cholinergic Agents
Oocytes
Pharmacology

Keywords

  • α9α10 receptors
  • Acetylcholine
  • Efferent system
  • Ion channels
  • Nicotinic receptors
  • Ryanodine

ASJC Scopus subject areas

  • Otorhinolaryngology
  • Physiology

Cite this

Ryanodine is a positive modulator of acetylcholine receptor gating in cochlear hair cells. / Zorrilla De San Martín, Javier; Ballestero, Jimena; Katz, Eleonora; Elgoyhen, A. Belén; Fuchs, Paul Albert.

In: JARO - Journal of the Association for Research in Otolaryngology, Vol. 8, No. 4, 12.2007, p. 474-483.

Research output: Contribution to journalArticle

Zorrilla De San Martín, Javier ; Ballestero, Jimena ; Katz, Eleonora ; Elgoyhen, A. Belén ; Fuchs, Paul Albert. / Ryanodine is a positive modulator of acetylcholine receptor gating in cochlear hair cells. In: JARO - Journal of the Association for Research in Otolaryngology. 2007 ; Vol. 8, No. 4. pp. 474-483.
@article{25ab72432bef4a99b8a3b57ad30ea913,
title = "Ryanodine is a positive modulator of acetylcholine receptor gating in cochlear hair cells",
abstract = "The efferent synaptic specialization of hair cells includes a near-membrane synaptic cistern, whose presence suggests a role for internal calcium stores in cholinergic inhibition. Calcium release channels from internal stores include 'ryanodine receptors', whose participation is usually demonstrated by sensitivity to the eponymous plant alkaloid, ryanodine. However, use of this and other store-active compounds on hair cells could be confounded by the unusual pharmacology of the α9α10-containing hair cell nicotinic cholinergic receptor (nAChR), which has been shown to be antagonized by a broad spectrum of compounds. Surprisingly, we found that ryanodine, rather than antagonizing, is a positive modulator of the α9α10 nAChR expressed in Xenopus oocytes, the first such compound to be found. The effect of ryanodine was to increase the apparent affinity and efficacy for acetylcholine (ACh). Correspondingly, ACh-evoked currents through the isolated cholinergic receptors of inner hair cells in excised mouse cochleas were approximately doubled by 200 μM ryanodine, a concentration that inhibits gating of the ryanodine receptor itself. This unusual positive modulation was not unique to the mammalian receptor. The response to ACh of chicken 'short' hair cells likewise was enhanced in the presence of 100 μM ryanodine. This facilitatory effect on current through the AChR could enhance brief (∼1 s) activation of associated calcium-dependent K+ (SK) channels in both chicken short hair cells and rat outer hair cells. This novel effect of ryanodine provides new opportunities for the design of compounds that potentiate α9α10- mediated responses and for potential inner ear therapeutics based on this interaction.",
keywords = "α9α10 receptors, Acetylcholine, Efferent system, Ion channels, Nicotinic receptors, Ryanodine",
author = "{Zorrilla De San Mart{\'i}n}, Javier and Jimena Ballestero and Eleonora Katz and Elgoyhen, {A. Bel{\'e}n} and Fuchs, {Paul Albert}",
year = "2007",
month = "12",
doi = "10.1007/s10162-007-0090-y",
language = "English (US)",
volume = "8",
pages = "474--483",
journal = "JARO - Journal of the Association for Research in Otolaryngology",
issn = "1525-3961",
publisher = "Springer New York",
number = "4",

}

TY - JOUR

T1 - Ryanodine is a positive modulator of acetylcholine receptor gating in cochlear hair cells

AU - Zorrilla De San Martín, Javier

AU - Ballestero, Jimena

AU - Katz, Eleonora

AU - Elgoyhen, A. Belén

AU - Fuchs, Paul Albert

PY - 2007/12

Y1 - 2007/12

N2 - The efferent synaptic specialization of hair cells includes a near-membrane synaptic cistern, whose presence suggests a role for internal calcium stores in cholinergic inhibition. Calcium release channels from internal stores include 'ryanodine receptors', whose participation is usually demonstrated by sensitivity to the eponymous plant alkaloid, ryanodine. However, use of this and other store-active compounds on hair cells could be confounded by the unusual pharmacology of the α9α10-containing hair cell nicotinic cholinergic receptor (nAChR), which has been shown to be antagonized by a broad spectrum of compounds. Surprisingly, we found that ryanodine, rather than antagonizing, is a positive modulator of the α9α10 nAChR expressed in Xenopus oocytes, the first such compound to be found. The effect of ryanodine was to increase the apparent affinity and efficacy for acetylcholine (ACh). Correspondingly, ACh-evoked currents through the isolated cholinergic receptors of inner hair cells in excised mouse cochleas were approximately doubled by 200 μM ryanodine, a concentration that inhibits gating of the ryanodine receptor itself. This unusual positive modulation was not unique to the mammalian receptor. The response to ACh of chicken 'short' hair cells likewise was enhanced in the presence of 100 μM ryanodine. This facilitatory effect on current through the AChR could enhance brief (∼1 s) activation of associated calcium-dependent K+ (SK) channels in both chicken short hair cells and rat outer hair cells. This novel effect of ryanodine provides new opportunities for the design of compounds that potentiate α9α10- mediated responses and for potential inner ear therapeutics based on this interaction.

AB - The efferent synaptic specialization of hair cells includes a near-membrane synaptic cistern, whose presence suggests a role for internal calcium stores in cholinergic inhibition. Calcium release channels from internal stores include 'ryanodine receptors', whose participation is usually demonstrated by sensitivity to the eponymous plant alkaloid, ryanodine. However, use of this and other store-active compounds on hair cells could be confounded by the unusual pharmacology of the α9α10-containing hair cell nicotinic cholinergic receptor (nAChR), which has been shown to be antagonized by a broad spectrum of compounds. Surprisingly, we found that ryanodine, rather than antagonizing, is a positive modulator of the α9α10 nAChR expressed in Xenopus oocytes, the first such compound to be found. The effect of ryanodine was to increase the apparent affinity and efficacy for acetylcholine (ACh). Correspondingly, ACh-evoked currents through the isolated cholinergic receptors of inner hair cells in excised mouse cochleas were approximately doubled by 200 μM ryanodine, a concentration that inhibits gating of the ryanodine receptor itself. This unusual positive modulation was not unique to the mammalian receptor. The response to ACh of chicken 'short' hair cells likewise was enhanced in the presence of 100 μM ryanodine. This facilitatory effect on current through the AChR could enhance brief (∼1 s) activation of associated calcium-dependent K+ (SK) channels in both chicken short hair cells and rat outer hair cells. This novel effect of ryanodine provides new opportunities for the design of compounds that potentiate α9α10- mediated responses and for potential inner ear therapeutics based on this interaction.

KW - α9α10 receptors

KW - Acetylcholine

KW - Efferent system

KW - Ion channels

KW - Nicotinic receptors

KW - Ryanodine

UR - http://www.scopus.com/inward/record.url?scp=35848969802&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35848969802&partnerID=8YFLogxK

U2 - 10.1007/s10162-007-0090-y

DO - 10.1007/s10162-007-0090-y

M3 - Article

C2 - 17647061

AN - SCOPUS:35848969802

VL - 8

SP - 474

EP - 483

JO - JARO - Journal of the Association for Research in Otolaryngology

JF - JARO - Journal of the Association for Research in Otolaryngology

SN - 1525-3961

IS - 4

ER -