BK Channels Mediate Cholinergic Inhibition of High Frequency Cochlear Hair Cells

Wersinger, Eric; McLean, Will J.; Fuchs, Paul; Pyott, Sonja J.

doi:10.1371/journal.pone.0013836

Cited by 67 publications

(72 citation statements)

References 59 publications

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“…Because efferent synaptic inhibition acts as a parallel shunt, the inhibitory conductance must increase with "resting" membrane conductance to remain effective. Thus, larger synaptic contacts in the high-frequency basal region might be expected, as has been reported previously (46). Moreover, the fact that RT-PCR and in situ hybridization measurement of α9 expression shows both longitudinal and radial gradients, with the greatest expression over OHCs in basal regions (48), might indicate a higher density of nAChRs in the high-frequency region of the cochlea.…”

Section: Discussionsupporting

confidence: 64%

“…However, the increasingly calcium-permeable nAChR of rat cochlear hair cells might also indicate that stronger efferent inhibition is required for mammalian cochlear hair cells. It has been observed (44)(45)(46) and recently elaborated (47) that OHCs exhibit increasing membrane ionic conductance moving from apical, low-frequency positions to higher-frequency basal locations in the mammalian cochlea. This increased membrane conductance along with decreased capacitance (membrane area) confers shorter membrane time constants to high-frequency basal OHCs.…”

Section: Discussionmentioning

confidence: 94%

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Phylogenetic differences in calcium permeability of the auditory hair cell cholinergic nicotinic receptor

Lipovsek

Franchini

et al. 2012

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

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The α9 and α10 cholinergic nicotinic receptor subunits assemble to form the receptor that mediates efferent inhibition of hair cell function within the auditory sensory organ, a mechanism thought to modulate the dynamic range of hearing. In contrast to all nicotinic receptors, which serve excitatory neurotransmission, the activation of α9α10 produces hyperpolarization of hair cells. An evolutionary analysis has shown that the α10 subunit exhibits signatures of positive selection only along the mammalian lineage, strongly suggesting the acquisition of a unique function. To establish whether mammalian α9α10 receptors have acquired distinct functional properties as a consequence of this evolutionary pressure, we compared the properties of rat and chicken recombinant and native α9α10 receptors. Our main finding in the present work is that, in contrast to the high (pCa 2+ /pMonovalents ∼10) Ca 2+ permeability reported for rat α9α10 receptors, recombinant and native chicken α9α10 receptors have a much lower permeability (∼2) to this cation, comparable to that of neuronal α4β2 receptors. Moreover, we show that, in contrast to α10, α7 as well as α4 and β2 nicotinic subunits are under purifying selection in vertebrates, consistent with the conserved Ca 2+ permeability reported across species. These results have important consequences for the activation of signaling cascades that lead to hyperpolarization of hair cells after α9α10 gating at the cholinergic-hair cell synapse. In addition, they suggest that high Ca 2+ permeability of the α9α10 cholinergic nicotinic receptor might have evolved together with other features that have given the mammalian ear an expanded high-frequency sensitivity.evolution | ionotropic receptor | ligand-gated channel | outer hair cell N icotinic cholinergic receptors (nAChRs) are transmembrane allosteric proteins involved in the physiological responses to the neurotransmitter acetylcholine (ACh) (1). They are assembled from five identical (homopentamer) or different (heteropentamer) polypeptide chains arranged symmetrically around a central axis that lines a channel pore (1). The selective pressures for maintaining a wide diversity of nAChR subunits remain unknown (2, 3). The pentameric structure and function of muscle nAChR is well established; however, although much progress has been achieved, the possible combinatorial assemblies of neuronal subunits and their stoichiometry, distribution and function in the central nervous system remain subjects of ongoing investigation (4). Uniquely among these nonmuscle nAChRs, a clear function has been identified for the α9 and α10 nAChR subunits. These subunits assemble to form a pentameric receptor with a likely α9 2 α10 3 stoichiometry, which serves cholinergic neurotransmission at the synapse between efferent fibers and hair cells of the auditory and vestibular end organs (5-8). Efferent function has been studied in cochlear hair cells, where it is thought to inhibit outer hair cell (OHC) electromotility and so reduce cochlear amplification (9). In co...

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 94%

Phylogenetic differences in calcium permeability of the auditory hair cell cholinergic nicotinic receptor

Lipovsek

Franchini

et al. 2012

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

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“…Thus, we expect that relative contamination of the I K we measure by I K,n will be small. Interestingly, Wersinger et al (49) found that linoperdine at 100 -200 M was able to substantially block outward K ϩ currents in apical OHCs and suggested that KCNQ4 channels underlie the major component of the outward I K . It must be emphasized, however, that this drug will block both Kv2.…”

Section: C302mentioning

confidence: 99%

Extracellular chloride regulation of Kv2.1, contributor to the major outward Kv current in mammalian outer hair cells

Surguchev²,

Bian³

et al. 2012

American Journal of Physiology-Cell Physiology

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Outer hair cells (OHC) function as both receptors and effectors in providing a boost to auditory reception. Amplification is driven by the motor protein prestin, which is under anionic control. Interestingly, we now find that the major, 4-AP-sensitive, outward K+ current of the OHC ( IK) is also sensitive to Cl−, although, in contrast to prestin, extracellularly. IK is inhibited by reducing extracellular Cl− levels, with a linear dependence of 0.4%/mM. Other voltage-dependent K+ (Kv) channel conductances in supporting cells, such as Hensen and Deiters' cells, are not affected by reduced extracellular Cl−. To elucidate the molecular basis of this Cl−-sensitive IK, we looked at potential molecular candidates based on Cl− sensitivity and/or similarities in kinetics. For IK, we identified three different Ca2+-independent components of IK based on the time constant of inactivation: a fast, transient outward current, a rapidly activating, slowly inactivating current ( Ik1), and a slowly inactivating current ( Ik2). Extracellular Cl− differentially affects these components. Because the inactivation time constants of Ik1 and Ik2 are similar to those of Kv1.5 and Kv2.1, we transiently transfected these constructs into CHO cells and found that low extracellular Cl− inhibited both channels with linear current reductions of 0.38%/mM and 0.49%/mM, respectively. We also tested heterologously expressed Slick and Slack conductances, two intracellularly Cl−-sensitive K+ channels, but found no extracellular Cl− sensitivity. The Cl− sensitivity of Kv2.1 and its robust expression within OHCs verified by single-cell RT-PCR indicate that these channels underlie the OHC's extracellular Cl− sensitivity.

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“…In contrast to this, the relative Ca 2+ to monovalent cation permeability ratio for the chicken recombinant 910 nAChR is much lower, a ratio of 2, which is similar to other nAChRs that do not contain the 910 subunits (50). The authors conclude that the evolutionary processes that were responsible for the increased Ca 2+ permeability of mammalian 910 nAChRs were specific to the mammalian lineage and happened concomitant with other adaptations that conferred high frequency hearing to mammals [27,[48][49][50] .…”

Section: Functions Of α9α10 Nicotinic Acetylcholine Receptorsmentioning

confidence: 81%

“…Both in vitro an in vivo models of inactivation of α9 nAChR-induced signaling using antagonists or RNA interference of keratinocyte as well as experiments in knockout mice delayed wound healing, and reduced colony scattering and In high frequency regions of the cochlea, in addition to the SK2 channels shown, BK channels (large conductance Ca 2+ and voltage-activated channels), are also expressed [48,49] . The ACh-induced conductance results in efferent modulation of the cell's excitability.…”

Section: Functions Of α9α10 Nicotinic Acetylcholine Receptorsmentioning

confidence: 99%

α9α10 Acetylcholine receptors: structure and functions

Vázquez

2016

Neurotransmitter

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The α9 and α10 nicotinic acetylcholine receptor (nAChR) subunits assemble as pentameric complexes with a central ligand-gated cation-selective pore. However, these subunits do not assemble with other nAChR subunits. The general topology of each subunit is similar to that of other ligand-gated, Cys-loop ion channels. Although the sequence and genomic organization of the α9 and α10 subunits determined their classification as nicotinic subunits, α9α10 nAChRs exhibit peculiar pharmacological properties that are not common to other nicotinic or muscarinic receptors. α9α10 nAChRs are expressed in diverse tissues, including auditory sensory hair cells, afferent neurons in the vestibular sensory organs, neurons of the dorsal root ganglion, skin, and bronchial epithelia. Furthermore, it has become apparent that nAChRs containing α9 and α10 subunits play essential roles in various physiological processes. For example, α9 is required for the normal development of the efferent synapses in the inner ear, and after the onset of hearing α9α10 nAChRs serve as the unique source of extracellular calcium for Ca 2+ -activated potassium channels in mature auditory hair cells. The development of drugs that selectively target α9/α10 receptors promises to be of therapeutic benefit since these receptors have distinct physiologic functions. They hold promise as pharmacological targets to treat complex auditory and vestibular pathologies, neuropathic pain, and pathologies of the skin and bronchia.

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BK Channels Mediate Cholinergic Inhibition of High Frequency Cochlear Hair Cells

Cited by 67 publications

References 59 publications

Phylogenetic differences in calcium permeability of the auditory hair cell cholinergic nicotinic receptor

Phylogenetic differences in calcium permeability of the auditory hair cell cholinergic nicotinic receptor

Extracellular chloride regulation of Kv2.1, contributor to the major outward Kv current in mammalian outer hair cells

α9α10 Acetylcholine receptors: structure and functions

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