Arch. Pharm. Res. DOI 10.1007/s12272-014-0411-8

REVIEW

Voltage-gated K+ channels contributing to temporal precision at the inner hair cell-auditory afferent nerve fiber synapses in the mammalian cochlea Min-Ho Oak • Eunyoung Yi

Received: 26 February 2014 / Accepted: 9 May 2014 Ó The Pharmaceutical Society of Korea 2014

Abstract To perform auditory tasks such as sound localization in the space, auditory neurons in the brain must distinguish sub-millisecond temporal differences in signals from two ears. Such high temporal resolution is possible when each neuron in the ascending auditory pathway fires brief action potential at very accurate timing. Various preand postsynaptic machineries ensuring such high temporal precision of auditory synaptic transmission have been identified. Of particular, in this review, the role of K? channels in shortening the duration of synaptic potentials will be discussed. First, the contribution of K? channels to AP firing of general auditory neurons will be discussed. Then, the focus will be moved to the inner hair cell (IHC)auditory afferent nerve fiber (ANF) synapses, the first synapses of ascending auditory pathway. Molecular and immunohistological techniques have revealed various K? channels in the cell bodies and their processes of ANFs. Since the development of patch-clamp recordings from the ANF dendrites in 2002, it became possible to monitor the IHC-ANF synaptic transmission in greater detail. As revealed in brain auditory synapses, several different K? channels appear to participate in reducing the duration of synaptic potentials at the IHC-ANF synapses. In addition, K? channels at the ANF dendrites might act as potential targets of efferent feedback from the brain. The hypothesis is that, upon loud sound exposure, efferent neurotransmitters released onto the ANF dendrites activate certain K? channels and prevent excitotoxicity of ANFs. Therefore, K? channels of the ANF dendrites might provide potential

M.-H. Oak  E. Yi (&) College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, 1666 Yeongsan-ro, Cheonggye-Myeon, Muan, Jeonnam 534-729, Republic of Korea e-mail: [email protected]

sites of pharmacological actions to prevent noise-induced hearing loss. Keywords Cochlea  Hair cell synapse  K? channel  Synaptic potential  Action potential generation

Introduction The cochlea of the inner ear is the site where the sound wave is translated into electrical signals. The sound entering the ear causes sequential movement of the tympanic membrane, the ossicles, and the stereociliary bundles of sensory hair cells, resulting in neurotransmitter release from the hair cells. The most peripheral auditory afferent neurons, also called the auditory afferent nerve fibers (ANFs), are bipolar cells with the peripheral process contacting sensory hair cell and the central process projecting to the ipsilateral cochlear nucleus of the brainstem (Kiang et al. 1982; Ryugo and May 1993). The CN neurons in turn project to various neurons in the ipsi- and contralateral auditory nuclei for further processing of the signals (Fig. 1). To perform normal auditory tasks, the auditory neurons in ascending pathway are specially optimized to detect very brief temporal differences in successive incoming signals. For example, auditory neurons can determine the direction of the sound source by distinguishing hundreds lsec differences in ascending signals from two ears (Mathews et al. 2010). Such high temporal resolution is possible only when auditory neurons along the ascending pathway are capable of firing very brief action potentials (APs) with very little temporal jitter (Golding and Oertel 2012; Trussell 1997). Indeed, numerous studies have shown that auditory synapses in the CNS are equipped with various pre- and

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Fig. 1 An overview of ascending auditory pathway. Sound entering the ear causes the vibration of tympanic membrane (TM). Through ossicular connections this movement is delivered into the cochlea. Sensory hair cells in the cochlea detect the vibration and release neurotransmitters accordingly. ANFs then carry the signal to neurons in the cochlear nucleus (CN) in the brainstem. Cochlear nucleus neurons ipsi- and contralaterally project to several auditory nuclei

[lateral superior olive (LSO), medial superior olive (MSO), medial nucleus of trapezoid body (MNTB) and lateral nucleus of trapezoid body (LNTB)] within the brainstem. Auditory brainstem neurons project to the inferior colliculus (IC) and the dorsal nucleus of the lateral lemniscus (DNLL). The signals then delivered to higher auditory centers for auditory information processing. The area marked with yellow rectangle is illustrated in Fig. 2 in larger image

postsynaptic machineries for high temporal resolution. Presynaptic nerve terminals of auditory neurons contain neurotransmitter release mechanisms enabling rapid release of multiple synaptic vesicles in well-coordinated manner (Schneggenburger and Forsythe 2006). Postsynaptically, auditory neurons express the neurotransmitter receptor with fast gating kinetics (Trussell et al. 1993; Postlethwaite et al. 2007; Gardner et al. 1999). Also, these neurons express various voltage-gated ion channels, especially a variety of K? channels reducing membrane response time (Bal and Oertel 2001; Cao et al. 2007). Combined together, these pre- and postsynaptic mechanisms produce large and brief synaptic potentials that can cross AP threshold without much temporal summation. Indeed, the duration of synaptic potential recorded in auditory brainstem synapses were only a few milliseconds (Ferragamo et al. 1998; Golding and Oertel 2012), (compared to several hundreds milliseconds in many non-auditory CNS neurons) and the firing rate of APs could reach up to kHz range (Yang et al. 2007; Macica et al. 2003). It is natural to expect the presence of similar pre- and postsynaptic mechanisms at the first ascending auditory synapse (Fig. 2). Without temporally accurate information from the first synapse, proper processing of the auditory information in later synapses would be challenging, no

matter how well equipped they are. Here, this review will discuss the characteristics of the synapse between the sensory hair cell and ANF since it is the first site where sound waves are encoded into electrical signals, in the form of APs of ANFs. The main focus will be on the voltagegated K? channels of ANFs that enable high temporal resolution signaling. Before discussing the K? channels in ANFs, we will introduce (1) the basic biophysical principles on how activities of ion channels, especially of K? channels, reduce membrane response time of a neuron, (2) types and properties of K? channels participating in improving temporal precision of brain auditory synapses, (3) the characteristics of hair cell-ANF synapses. Then, the kinds of K? channels present in ANFs and their role in temporal resolution of hair cell-ANF synapses will be described. Finally, pharmacological perspectives of K? channels of ANF in preventing noise-induced hearing loss will be mentioned.

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K1 channels reduce membrane response time From a simplified biophysical point, a cell can be viewed as a simple electrical circuit (Fig. 3A) composed of a

Voltage-gated K? channels contributing to temporal precision

Fig. 2 The IHC-ANF synapse in the mammalian cochlea. A Simplified illustration of the auditory afferent innervation to the IHC. View from the apex of the cochlear coil. Each IHC is contacted by *10–30 ANFs. Each ANF innervates only one IHC via single dendritic terminal. B Synaptic organization and ion channel expression in the dendrite of an ANF. ANF is a bipolar neuron with its peripheral process contacting single IHC and the central process projecting to the cochlear nucleus of the brain. The cluster of the cell bodies of ANFs, often called the spiral ganglion (SG), is located in the middle of the cochlear coil. Except its dendritic segment (*50 lm), both processes of an ANF are myelinated. In many mammalian species

including rats and mice, the cell body of ANF is also myelinated. Efferent nerve fibers originated from the LOC of the brain contact the unmyelinated segment of the ANF peripheral process. The unmyelinated dendritic segment of an ANF express voltage-gated Na? channel (NaV), hyperpolarization-activated cyclic nucleotide gated cation channel (Ih), low-voltage activating K? channels (LVK) and high-voltage activating K? channels (HVK). High density expression of NaV channels is observed at the first heminode (*) of ANF. It has been postulated that these voltage-gated ion channels might be the targets of LOC efferent modulation

resistor (Rm) and a capacitor (Cm). Upon current injection, the membrane potential of this cell will show exponential change (Fig. 3B). The speed of membrane potential change (sm) in this cell can be expressed as a function sm = Rm*Cm. Cm is proportionate to the surface area of lipid bilayer membrane and thus, relatively constant for any given short period of time, except during significant cell morphological changes such as cell division or process outgrowth. Rm, on the other hand, can be much more variable. Ion channels on cell membrane provide additional passages for ions to flow through and dramatically change Rm. By modulating the type, number and activity level of ion channels expressed on the membrane, therefore, a cell can modulate Rm. As illustrated in Fig. 3B, when the membrane resistance is changed to 2Rm, the speed of membrane response time will be doubled. If the membrane resistance is reduced to 1/2Rm, the speed of membrane response time will be decreased accordingly. Although opening of any kind of ion channels can virtually decrease Rm and sm, the role of K? channels on Rm in auditory neurons have been more frequently

investigated. Unlike Ca2? or Na? channels, many K? channels are at least partially active at resting state of a cell (*-60 to -70 mV in neurons) and their influence on Rm can be more extensive than that of others. Depending on the operational mechanism and structures K? channels (Fig. 4) are classified into 4 large groups (Gutman et al. 2005; Kubo et al. 2005; Wei et al. 2005; Goldstein et al. 2005); voltage-gated (Kv), Ca2? activated (KCa), inward rectifier (Kir), and 2-pore K? Channels (K2P). According to the genes encoding the pore-forming a subunit of K? channels, they are further subdivided into families and subfamilies, each designated with 2 numbers separated by a period (see Table 1). It takes an association of multiple a subunits (either homomeric or heteromeric association within the same family) for functional channel. The Kv, KCa, and Kir channels are tetramers whereas K2P channels are dimers. The electrophysiological properties such as voltage dependence, opening/closing kinetics, and single channel conductance, are extremely diverse according to the splice variant, subunit composition, and interaction with auxiliary subunits. To make matters even more

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complex intracellular signaling pathways can modify the properties of K? channels as well. The activity of K? channels have been shown to be modified through direct interaction with certain G proteins, phosphorylation by PKA or PKC, intracellular second messengers such as phosphoinositides, Ca2? and cyclic nucleotides (Goldstein et al. 2005; Gutman et al. 2005; Hibino et al. 2010; Honore 2007; Kubo et al. 2005).

Fig. 3 The time course of membrane potential changes of a simple model cell. Suppose that a current step stimulus is injected (A) into a simple model cell composed of a capacitor (Cm) and a resistor (Rm). The membrane potential of this cell will grow exponentially and then approach to a certain maximum (B, black line). sm is a measure of the speed of the membrane potential change and is equal to RmCm. The value is also equal to the time required to reach approximately 63 % of the maximum membrane potential. Now imagine a second model cell whose resistance is only half of the first cell (1/2 Rm; but capacitance is still Cm). When a current step stimulus is injected, the membrane potential of the second cell will also grow exponentially (B, red line). However, the time taking to the 63 % of its maximum (s0 ) will be shorter (s0 = 1/2 sm). Likewise, in a third cell with resistance 2Rm and capacitance Cm (B, blue line), it will take twice as much time to reach its 63 % of the maximum than in the first cell (s00 = 2 sm)

Fig. 4 Structure of K? channels. Predicted membrane topologies of pore-forming a subunits of K? channels are illustrated. A Kv channel subunits have 6 transmembrane domains, one pore-forming P loop between the fifth and sixth transmembrane domains and intracellular N- and C-termini. B Kir channel subunits have 2 transmembrane domains and a P loop between them. C Most KCa channel subunits, like Kv channels, have 6 transmembrane domains and a P loop

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Voltage-gated K1 channels contributing to high temporal resolution: lessons from brain auditory synapses As listed in Table 1, mRNAs or peptides of most known K? channel families have been found in various auditory neurons. Due to the reasons discussed above and a limited number of subtype-specific blockers, it is extremely difficult to measure out the exact amount of contribution by each K? channel on temporal resolution of auditory neurons. However, attempts have been made using pharmacological agents and transgenic animals lacking certain K? channel subunit. Generalized and perhaps oversimplified characteristics of each K? channel family are summarized

between the fifth and sixth transmembrane domains. KCa1.1, the subunit forming BK channels (also known as max-K channels), has one additional transmembrane domain near the N-terminus. D K2P channel subunits contain 4 transmembrane domains and 2 P loops. Functional Kv, Kir and KCa channels are tetramers whereas functional K2P channels are dimers

Voltage-gated K? channels contributing to temporal precision Table 1 K? channels controlling auditory neuron excitability IUPHAR

HGNC

Other

Species

location

Detection method

Reference

Kv1.1

KCNA1

Shaker-related

Mouse

MNTB, CN, SOC, IC

In situ

Grigg et al. (2000)

Mouse

MNTB

Immunohistology

Brew et al. (2003)

Mouse

MNTB

qRT PCR, Western

Brew et al. (2007)

Rat

MNTB

qRT PCR, pharmacology

Tong et al. (2010)

Rat

CN

qRT PCR, immunohistology

Bortone et al. (2006)

Chicken

CN

Immunohistology

Lu et al. (2004)

Mouse

LSO

Immunohistology

Karcz et al. (2011)

Mouse

SG

Immunohistology

Adamson et al. (2002)

Mouse

SG

qRT PCR

Chen and Davis (2006)

Mouse

SG

Immunohistology, pharmacology

Liu et al. (2014)

Kv1.2

KCNA2

Shaker-related

Mouse

SG

Immunohistology, pharmacology

Mo et al. (2002)

Mouse

MNTB, CN, SOC, IC

In situ

Grigg et al. (2000) Brew et al. (2003)

Mouse

MNTB

Immunohistology

Mouse

MNTB

qRT PCR, Western,

Brew et al. (2007)

Rat

MNTB

Pharmacology

Tong et al. (2010)

Mouse

CN

qRT PCR

Bortone et al. (2006)

LS

qRT PCR, immunohistology

Karcz et al. (2011)

Mouse

SG

Immunohistology

Wang et al. (2013)

Mouse

SG

Immunohistology

Liu et al. (2014)

Mouse

SG*

Immunohistology

Lacas-Gervais et al. (2004)

Immunohistology

Wang et al. (2013)

Kv1.4

KCNA4

Shaker-related

Mouse

SG

Kv2.1

KCNB1

Shab-related

Mouse

MNTB

qRT PCR

Johnston et al. (2008b)

Kv2.2

KCNB2

Shab-related

Mouse

MNTB, VNTB

qRT PCR, immunohistology

Johnston et al. (2008b)

Mouse

MNTB,VNTB

Immunohistology

Tong et al. (2013)

Kv3.1

KCNC1

Shaw-related

Mouse

MNTB,CN

In situ

Wang et al. (1998)

Mouse

MNTB,CN, SOC, IC

In situ

Grigg et al. (2000)

Mouse

MNTB

qRT PCR

Johnston et al. (2008a)

Mouse

MNTB, VNTB, LNTB,

Immunohistology

Zettel et al. (2007)

Rat

SPN, LSO

qRT PCR, immunohistology

Tong et al. (2010)

Rat

CN

qRT PCR,

Bortone et al. (2006)

Chicken

CN

Immunohistology

Lu et al. 2004

Mouse

SG

Immunohistology

Adamson et al. (2002)

Mouse

SG

qRT PCR

Chen and Davis (2006)

Mous

MNTB, CN, SOC, IC

In situ

Grigg et al. (2000)

Rat

MNTB

qRT PCR

Tong et al. (2010)

Mouse

SG

qRT PCR, immunohistology

Chen and Davis (2006)

Mouse

CN

RT PCR, in situ

Fitzakerley et al. (2000)

Mouse

MNTB

Immunohistolog

Johnston et al. (2008a)

Kv3.3

Kv4.2

KCNC3

KCND2

Shaw-related

Shal-related

Chicken

SG

In situ, immunohistolog

Sokolowski et al. (2004)

Mouse

SG

Immunohistology

Adamson et al. (2002)

Mouse

SG

qRT PCR

Chen and Davis (2006)

Mouse

CN

RT PCR, in situ

Fitzakerley et al. (2000)

Kv4.3

KCND3

Mouse

MNTB

Immunohistology

Johnston et al. (2008a)

Kv7.2

KCNQ2

Rat, Guinea pig

SG

RT PCR, immunohistology

Jin et al. (2009)

Kv7.3

KCNQ3

Rat, Guinea pig

SG

RT PCR, immunohistology

Jin et al. (2009)

Mouse

CN

Pharmacology

Li et al. (2013)

Mouse

SG

Immunohistology

Beisel et al. (2005)

Shal-related

Kv7.2/7.3 Kv7.4

KCNQ4

Kv7.5

KCNQ5

Kv11.1

KCNH2

erg1

Rat

Calyx of Held

Immunohistology

Huang and Trussell (2011)

Mouse

MNT

qRT PCR, immunohistology

Hardman and Forsythe (2009)

Mouse

SG

Immunohistology

Nie et al. (2005)

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M.-H. Oak, E. Yi Table 1 continued IUPHAR

HGNC

Other

Species

location

Detection method

Reference

Kv11.3

KCNH6

erg2

Mouse

MNTB

qRT PCR, immunohistology

Hardman and Forsythe (2009)

Kir5.1

KCNJ16

BIR9

Rat

SG

Immunohistology

Hibino et al. (2004)

KCa1.1

KCNMA1

Slo, BK

Guinea pig

SG

In situ, immunohistology

Skinner et al. (2003)

Mouse

SG

Immunohistology

Adamson et al. (2002)

Mouse

SG

qRT PCR

Chen and Davis (2006)

Mouse

SG

Immunohistology

Kathiresan et al. (2009)

KCa4.1

KCNT1

Slack, Slo2.2

Mouse

MNTB

Immunohistology

Yang et al. (2007)

KCa4.2

KCNT2

Slick, Slo2.1

Mouse

MNTB

Immunohistology

Yang et al. (2007)

K2P1.1

KCNK1

TWIK-1

Rate

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

K2P2.1

K2P3.1

K2P4.1

K2P6.1 K2P9.1

K2P10.1 K2P12.1

K2P13.1 K2P15.1

KCNK2

KCNK3

KCNK4

KCNK6 KCNK9

KCNK10 KCNK12

KCNK13 KCNK15

TREK-1

TASK-1

TRAAK

TWIK-2 TASK-3

TREK-2 THIK-2

THIK-1 TASK-5

Mous

SG

qRT PCR, immunohistology

Chen and Davis (2006)

Rat

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

Rat

CN

Immunohistology

Kanjhan et al. (2004a)

Rat

SG

Immunohistology

Kanjhan et al. (2004b)

mouse

SG

qRT PCR, immunohistology

Chen and Davis (2006)

Rat

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

Rat

CN

Immunohistology

Kanjhan et al. (2004a)

Mouse

SG

RT PCR

Chen and Davis (2006)

Rat

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

Mouse

SG

qRT PCR

Chen and Davis (2006)

Rat

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

Rat

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

Mouse

SG

qRT PCR

Chen and Davis (2006)

Rat

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

Rat

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

Mouse

SG

qRT PCR

Chen and Davis (2006)

Rat

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

Rat

IC

qRT PCR, in situ

Cui et al. (2007)

Rat

CN

qRT PCR

Holt et al. (2006)

IUPHAR International Union of Phamacology, HGNC HUGO Gene Nomenclature Committee, MNTB medial nucleus of the trapezoid body, VNTB ventral nucleus of the trapezoid body, LNTB lateral nucleus of the trapezoid body, SPN superior paraolivary nucleus, LSO lateral superior olive, CN cochlear nucleus, SG spiral ganglion, * near the first node of Ranvier of the SG neurons, qRT PCR quantitative RT PCR, in situ in situ hybridization

in Table 2. Although some frequently used pharmacological agents are listed in Table 2 as well, care must be taken because most of these agents exhibit only limited specificity, especially among K? channels within the same family. According to the voltage range at which the K? channels are active one might divide them into 2 categories, low-voltage and high-voltage activating K? channels. Significant fraction of low-voltage activating K? channels

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(LVKs) stay open at relatively negative membrane potential (-40 mV or more negative), even at rest (Johnston et al. 2010). Many channels in Kv1, Kv4, Kv7, Kv11, Kir and K2P families fall into this category. Several channels belonging to Kir and K2P families are known to be constitutively active, rather than gating upon voltage change (Honore 2007; Goldstein et al. 2005; Kubo et al. 2005). On the other hand, Kv channels in this category are gated by voltage changes (Gutman et al. 2005; Johnston et al. 2010).

Voltage-gated K? channels contributing to temporal precision Table 2 Electrophysiological properties and pharmacological profiles for K channels in auditory neurons Channel family

Electrophysiological properties

Pharmacological profile

Activation voltage

Gating characteristics

Blocker

Kv1

Low-voltage#

Fast activation

a-Dendrotoxin (Kv1.1, 1.2, 1.6)

Reference Activator Hopkins (1998), Brew et al. (2003), Brew et al. (2007), Klug and Trussell (2006), Gittelman and Tempel (2006), Mo et al. (2002), Wang et al. (2013)

Dendrotoxin-I (Kv1.1, 1.2, 1.6) Dendrotoxin-K (Kv1.1) Tityustoxin-Ka (Kv1.2) CP339818 (Kv1.3, 1.4) 4-AP* Kv2

High-voltage##

Slow activation

Stromatoxin

Johnston et al. (2010)

TEA** 4-AP* Kv3

High-voltage

Fast activation

BDS-I, 4-AP*, TEA**

Dhawan et al. (2010)

Kv4

Low-voltage

Fast activation

Phrixotoxin

Fast inactivation (A-type)

4-AP*

Johnston et al. (2010), Chagot et al. (2005)

Kv7

Low-voltage

Slow activation

Linopirdine

Kv11

Low-voltage

C-type inactivation Slow deactivation

E4031 BeKm-1

KCa1.1

High-voltage Modified by internal Ca2?

Fast activation

Iberiotoxin

Activated by internal Ca2?

Charybdotoxin

Low-voltage

Activated by intracellular Na?

Lithium substitution

Retigabine

Lv et al. (2010), Johnston et al. (2010) Nie et al. (2005), Hardman and Forsythe (2009)

Terfenadine

KCa4

Skinner et al. (2003), Wersinger et al. (2010)

TEA** TEA

Kir

Low-voltage Inward rectifier

Constitutively open Gated by 2nd messengers

External Ba2?, Cs? Internal Mg2?, polyamine

K2P

Open rectifier (active at rest)

Instantaneous activation and deactivation (open leak)

Ba2?, external pH Quinidine

Bithionol, loxapine

Yang et al. (2006), Bhattacharjee and Kaczmarek (2005), Kaczmarek (2013) Hibino et al. (2010), Kubo et al. (2005)

Volatile anesthetics

Honore (2007), Shin et al. (2013), Goldstein et al. (2005)

*, ** 4-AP and TEA are non-selective K? channel blockers but exhibit some degree of family selectivity in concentration-dependent manner (Gutman et al. 2005; Johnston et al. 2010) # Current considerably active at near -40 mV or more negative;

##

Whether constitutively active or voltage-gated, LVKs significantly lower Rm and thus reduce sm. Of particular, there have been many reports on contribution of Kv1 family channels to temporal precision of auditory synaptic transmission (Brew et al. 2003; Karcz et al. 2011; Gittelman and Tempel 2006; Klug and Trussell 2006). When Kv1 channels were blocked by dendrotoxins (Hopkins 1998), synaptic potentials in various brain auditory neurons were significantly prolonged (Fig. 5A). Transgenic mice lacking Kv1 channels (Brew et al. 2003; Kopp-Scheinpflug et al. 2003) exhibited hearing deficit due to weakened temporal resolution. Of note, auditory neurons were often found to co-express Kv1 channels and hyperpolarization-activated cyclic nucleotide-gated cation channels (Ih) (Oertel et al. 2008; Cao et al. 2007). As the name implies, Ih channels open upon membrane hyperpolarization, resulting in cation

Current considerably active at near -30 mV or more positive

influx and consequent membrane depolarization. Because their activation voltage range overlaps with Kv1 channels, membrane depolarization by Ih channels can facilitate Kv1 channel opening, which in turn bring about more Ih activation. Therefore, Kv1 and Ih channels appear to act synergistically in decreasing Rm and sm (Fig. 5A), and shortening the duration of synaptic potentials and APs (Rothman and Manis 2003a, b). High-voltage activating K? channels (HVK) open at much more depolarized voltage than resting membrane potential (-30 mV or more depolarized). Kv2 and Kv3 channels belong to this category (Gutman et al. 2005; Johnston et al. 2010). Due to their high-voltage activating property HVKs open primarily during AP firing (Fig. 5B), and participate in maintaining high frequency AP firing (Lu et al. 2004; Macica et al. 2003; Song and Kaczmarek

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Fig. 5 K? channels modulate the shape of EPSPs and APs. A LVK and Ih are active near resting membrane potential of auditory neurons and primarily keep the EPSPs brief. When LVK or Ih channel blockers are applied to an auditory neuron (such as dendrotoxins for blocking LVK and ZD7288 for inhibiting Ih), Rm of this neuron is significantly increased. Consequently, the amplitude of EPSP might become larger and the rise and decay time slower (blue line). B Both LVK and HVK open during AP firing. When LVK or HVK blockers are applied to an auditory neuron the shape of AP become much broader as well. Moreover, the AP timing (time to peak) becomes much more variable. Therefore, this neuron cannot fire APs at high rate and loses temporal precision

2006). Studies using low concentration tetraethylammonium (TEA, selectively blocks Kv3 channels at low concentration) (Johnston et al. 2010; Rothman and Manis 2003a) or mice lacking Kv3 channels (Macica et al. 2003) have demonstrated that Kv3 channels enable rapid repolarization and thus, are essential for high frequency firing. In addition, without proper actions of LVK and HVK, the timing of APs became much more variable. As illustrated in Fig. 5B, normal auditory neurons fire APs with very little jitter whereas neurons treated with K? channel blockers exhibit variable firing time. KCa channels are, with some degree of voltage-sensitivity, gated by intracellular cations such as Ca2? or Na?. Influx of Ca2? or Na? during AP firing seems to activate these channels, which in turn might facilitate repolarization and after spike hyperpolarization (Wei et al. 2005). Although belonging to KCa family KCa4 channels are activated by Na? (hence, often referred to as KNa channels) rather than Ca2? (Bhattacharjee and Kaczmarek 2005). In auditory neurons of MNTB, high frequency firing with good temporal precision appeared to be maintained in part by KCa4 channels (Yang et al. 2007).

Properties of IHC-ANF synapse In the mammalian cochlea, there are 2 types of sensory cells. The outer hair cells (OHCs), by receiving the efferent feedback signals from the brain, act as sensitivity-modulator rather than true sound-sensor. The IHCs, though fewer

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in numbers, appear to act as the sound-sensor (Berglund and Ryugo 1987). Over 90 % of the entire ANFs contact only IHCs. Each IHC is contacted by approximately 20 ANFs, via single dendritic terminals (Fig. 2A). Practically all auditory information entering the cochlea is thought to be first encoded at the IHC-ANF synapses. Like auditory synapses in the brain IHC-ANF synapses are equipped with multiple pre- and postsynaptic mechanisms enabling high temporal precision signaling. IHCs have special presynaptic structures called synaptic ribbon. The synaptic ribbons are composed of round or ovalshaped electron-dense protein core and synaptic vesicles tethered around the core (Fig. 2B). Normal anchoring of synaptic ribbons to the IHC membrane appeared critical in multivesicular release in well-coordinated manner, for prolonged period of time (Fuchs et al. 2003). Severe hearing deficit has been reported in animals with disrupted ribbon structure (Jing et al. 2013; Khimich et al. 2005). Glutamate released from IHCs is detected by AMPA type receptors on the dendritic terminal of ANF. Similar to AMPA receptors expressed in other auditory synapses, AMPA receptors on ANF dendrites exhibit fast gating kinetics (Glowatzki and Fuchs 2002; Goutman and Glowatzki 2011; Grant et al. 2010). Therefore, synaptic currents recorded at the IHC-ANF synapses were extremely brief, comparable to ones recorded in brain auditory synapses.

Voltage-gated K1 channels in ANF dendrites As listed in Table 1, mRNAs and peptides for diverse K? channels have been found in the somas of ANFs (also known as the spiral ganglion neurons) as well. It has been postulated that many K? channels, as described in brain auditory synapses, also participate in reducing Rm and sm of ANFs and thus, contribute to high temporal precision of IHC-ANF synapse. To test this hypothesis researchers often have employed electrophysiological recording techniques on isolated ANF somas. Using combinations of pharmacological agents the potential contribution of certain K? channel in determining the AP shape and firing pattern of ANFs has been demonstrated. For example, electrophysiological recordings have revealed the presence of LVK and HVK components in ANF somas (Mo et al. 2002; Lv et al. 2010; Liu et al. 2014; Adamson et al. 2002; Wang et al. 2013). The LVK component in ANF soma was sensitive to 4-AP (at concentration appeared to be selective to LVK in brain auditory synapses). Furthermore, the majority of LVK component was inhibited by dendrotoxins, the selective Kv1 family blocker (Wang et al. 2013; Mo et al. 2002). These results indicate that LVK in ANF soma is predominantly composed of Kv1 family channels. Analysis of APs recorded in dendrotoxin-treated ANF somas

Voltage-gated K? channels contributing to temporal precision

also suggested that Kv1 channels participate in determining the resting membrane potential, AP threshold and firing pattern of ANFs (Mo et al. 2002). In addition to Kv1 channels, ANF somas express dendrotoxin-insensitive LVK component. The sensitivity to linopirdine and retigabine (Lv et al. 2010) suggested that dendrotoxin-insensitive LVK is, at least in part, composed of Kv7 family channels. As often observed in brain auditory neurons, ANF somas co-express LVK and Ih (Liu et al. 2014). The activity voltage range of Ih in ANF soma also significantly overlaps with LVK. LVK and Ih appeared to act synergistically in determining Rm and firing properties of ANF soma. HVK components in ANF soma were mostly blocked by low concentration of TEA, suggesting involvement of Kv3 channels (Szabo et al. 2002). Despite lack of data obtained with more Kv3-selective agents, combined analysis of electrophysiological and semi-quantitative immunohistochemical data strongly supported significant involvement of Kv3 channels in determining the AP shape and firing properties of ANF somas (Adamson et al. 2002). Recordings from the dendritic terminals of ANFs in semi-intact cochlear preparations have revealed somewhat similar pattern of K? channel activity. ANF dendrites contained 4-AP-sensitive LVK, TEA-sensitive HVK, and Ih at the IHC-ANF synapses (Yi and Glowatzki 2006). LVK and Ih (Yi et al. 2010) at the ANF dendrites, as predicted from the soma recordings, significantly reduced the duration of synaptic potentials and hence, appeared to enhance temporal precision of IHC-ANF synaptic transmission. However, some precaution must be taken in applying information from ANF soma, to IHC-ANF synapses. Most ANF soma recordings, though providing extremely valuable data for understanding some firing properties of ANFs, were obtained from isolated ANF neurons without peripheral and central processes (Mo et al. 2002; Lv et al. 2010; Liu et al. 2014; Adamson et al. 2002; Wang et al. 2013). In this type of recording configuration, it was not possible to monitor APs evoked by IHC-derived synaptic stimuli. Unlike many brain auditory neurons, the AP initiation zone of ANFs is localized near the end of ANF peripheral process (Fig. 2B, * first heminode), several hundreds lm away from the soma (Hossain et al. 2005). For a better access of recording electrode, in most soma recordings, isolated and cultured ANFs had been used. As illustrated in Fig. 2B, most surfaces of ANFs, in vivo, are covered with myelin sheath, making access of electrophysiological recording electrodes to the somas very difficult. When kept in culture media for 1–2 days, the myelin sheath surrounding ANF soma becomes loose (Wang et al. 2013). In some of those studies, ANFs were isolated from neonatal rodents (Adamson et al. 2002; Mo et al. 2002), at the age the myelin sheath is still incompletely formed

around the soma. Therefore, the APs, evoked by artificially injected stimuli, recorded far away from their natural AP initiation zone, and often in immature neurons, might not accurately depict all the properties of APs evoked by IHCsynaptic stimuli. In fact, there have been reports indicating that biophysical properties of the soma and the dendrite of the same neuron might not be identical. In vestibular afferent nerve fibers whose morphology and biophysical characteristics are quite similar to ANFs, the somatic LVK was predominantly dendrotoxin-sensitive, whereas the dendritic LVK appeared to be largely dendrotoxin-insensitive (Dhawan et al. 2010; Rennie and Streeter 2006). To accurately measure the degree of contribution by each K? channels to temporal precision of IHC-ANF synapses, ANF dendritic recordings in combination with pharmacological agents are, by far, the most direct method. The K? channels, whose somatic expression had been shown by molecular biological techniques (Adamson et al. 2002; Chen and Davis 2006), are the most obvious targets of next investigation. Yet, due to limited number of subtype-selective pharmacological agents, additional techniques such as high resolution microscopy would be necessary to confirm the dendritic location of candidate channel subunits. Currently, the candidates of interest are: Kv3 for HVK, Kv1 for dendrotoxin-sensitive LVK, and Kv7, Kv11, and Kir channels for the remaining LVK. Perspectives Is there any advantage in expressing such diverse K? channels at the ANF dendrites? It is not difficult to expect that K? channels with such diverse voltage-dependence and gating kinetics could help maintain low Rm and sm and therefore, shorten the duration of synaptic potentials and APs. However, the key to answer the question might lie in the fact that the activities of many aforementioned K? channels can be modified by a variety of intracellular signaling pathways. One of the long-standing enigmas in auditory science is the physiology of efferent nerve fibers innervating IHCANF synapses (Simmons 2002). Through anatomical studies, a presence of efferent nerve fibers to IHC-ANF synapses has been known for long time. These efferent fibers are originated from the lateral olivary complex (LOC) of the brainstem and directly contact ANF dendrites (Fig. 2B), but not IHCs. Diverse neurotransmitters such as acetylcholine, GABA, dopamine and opioid peptides have been found in the LOC efferent nerve fibers (Safieddine et al. 1997). Receptors for LOC neurotransmitters, even multiple subtypes for the same neurotransmitter, have been found at the somas and dendrites of ANFs (Maison et al. 2012). It has been postulated that LOC efferent nerve fibers

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play important role in enhancing the detection sensitivity to interaural time difference (Darrow et al. 2006) or exhibit protective role against noise-induced hearing loss (Darrow et al. 2007). However, the exact mechanism for such function remains largely unidentified. It would be interesting to find out if there is any specific receptor-K? channel partnership at the ANF dendrites. Via LOC efferent modulation of certain K? channels, extremely finetuning of ANF excitability could be possible. Also, an identification of K? channel modifying-intracellular pathway at the ANF dendrites would provide unique opportunity to devise pharmacological strategies against noise-induced hearing deficit. Exposing animals to loud noise have been shown to induce acute excitotoxicity in the IHC-ANF synapses. Although the noise-exposure may not cause immediate death in hair cells and ANFs it could lead to significant disruption of IHC-ANF synaptic structures, often in the form of swellings and retractions of ANF dendrites (Kujawa and Liberman 2009). The IHCANF synaptopathy associated with ANF dendritic retractions appears to be an irreversible phenomenon in adult animals and is considered to be contributing factor to noise-induced auditory anomalies such as tinnitus. Conceptually, over-excited state of ANFs can be alleviated by a controlled enhancement of activities of certain K? channels in ANF dendrites. Delivering a pharmacological agent (either directly modifying certain K? channel activities or indirectly modulating receptor-coupled K? channels) to the IHC-ANF synapses upon noise exposure might, therefore, provide a preventive measure against noise-induced hearing deficit.

Conclusions An overview on the types, structure and physiological functions of various K? channels expressed in auditory neurons has been presented. All 4 groups of K? channels, namely Kv, KCa, Kir, K2P channels, have been found in brain auditory neurons as well as in the peripheral ANFs. These K? channels, by decreasing the Rm of postsynaptic membrane, reduce membrane response time and shorten the duration of EPSPs and APs. K? channels also participate in decreasing temporal jitter of APs. The evidence all indicates that K? channels in auditory synapses are playing critical role in improving temporal resolution of the auditory synaptic transmission. In addition, a potential involvement of K? channels in LOC efferent feedback modification at the IHC-ANF synapses has been postulated. Identification of specific receptor-K? channel partnership at the IHC-ANF synapses might lead us to pharmacological strategies against noise-induced excitotoxicity in ANF dendrites and noise-induced hearing deficit.

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Acknowledgments This paper was supported in part by Research Funds of Mokpo National University in 2011. Conflict of interest

There is no conflict of interest.

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