Microsoft Word doc

Size: px

Start display at page:

Download "Microsoft Word doc"

유걸 종
7 years ago
Views:

1 Review online ML Comm Korean J Otorhinolaryngol-Head Neck Surg 2010;53: / DOI /kjorl-hns pissn / eissn Homeostasis in the Inner Ear Sung Huhn Kim and Sang Cheol Kim Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea 김성헌 김상철 연세대학교의과대학이비인후과학교실 Address for correspondence Sung Huhn Kim, MD Department of Otorhinolaryngology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul , Korea Tel Fax fledermaus@yuhs.ac homeostasis in the inner ear is important to maintain normal hearing and balance. transport in the inner ear is reported to be occurred in non-sensory epithelium of inner ear which forms a barrier between endolymphatic space and perilymphatic space. Functionally identified and constitutively active absorption sites in the inner ear are Reissner s membrane, outer sulcus cells, vestibular transitional cells, saccular nonsensory epithelial cells, and endolymphatic sac epithelial cells. transport in these epithelial cells is mediated by apically located epithelial channels (ENaC), nonselective cation channels and basolaterally located, - ATPase. absorption is increased by glucocorticoid through glucocorticoid receptor or ATP through purinergic receptors depending on cell types. Korean J Otorhinolaryngol-Head Neck Surg 2010;53: Key WordsZZSodium Homeostasis Inner ear Cochlear Vestibule Endolymphatic sac. 내이는와우 (cochlea) 와전정 (vestibule) 및내림프낭 (endolymphatic sac) 으로구성되어있으며, 청각과인체의평형을담당하는구조이다. 이들은측두골내에위치하고있으며, 막성구조로이루어져있어막성미로 (membranous labyrinth) 라고하며, 그주위를측두골의골성미로 (bony labyrinth) 가둘러싸고있다. 막성미로는 농도가높고 농도가낮은내림프로채워져있으며, 이를내림프공간 (eodnlymphatic space) 이라고하고, 골성미로와막성미로사이는 농도가높고 농도가낮은외림프로채워져있으며, 이를외림프공간 (perilymphatic space) 이라고하는데, 이러한두공간의림프액조성의차이는매우독특하며 (Table 1), 1,2) 이는소리와두부의회전혹은직선가속도자극에반응하여신경전도를일으켜중추신경계로전달하는데중요한환경을제공한다. 내림프공간을둘러싼막성미로는다양한종류의특화된상피세포로구성되어있어외림프공간과내림프공간의경계를형성하는데, 이들상피세포는소리와가속감각을전기신호로전 환하는와우와전정의감각상피 (sensory epithelium) 와그외의비감각성상피 (non-sensory epithelium) 로구성되어있다. 감각상피인유모세포 (hair cell) 에서는소리나회전혹은직선가속도자극에의해유발되는내림프의진동및흐름이있을때유모세포의섬모 (stereocilia) 로 이유입되어세포가탈분극이되고, 이는 Ca 2+ 의유입을촉진시켜세포기저부에서신경전달물질을유리시켜와우및전정신경의탈분극을일으켜감각을전달하며, 3) 비감각성상피세포는내림프와외림프에존재하는이온의이동을담당하여두임파액의항상성을유지하는역할을하는것으로알려져있다. 2) 이온이내림프공간에서감각전달을위한주요전위를일으키는이온이지만, 유모세포의섬모에존재하여 을유입하는채널이비선택적양이온채널 (mechano-sensative non-selective cation channel) 이기때문에, 4) 유모세포의기능을유지하기위해서는 과 Ca 2+ 의농도또한일정하게유지되는것이중요하다. 만약 과 Ca 2+ 의농도가높게유지되어유모세포로유입된이들의농도가비정상적으로유지될경우는유모세포의기능부전을초래하여난청이나평형기능장애를초래할수있다. 하지 Copyright c 2010 Korean Society of Otorhinolaryngology-Head and Neck Surgery 399

2 Korean J Otorhinolaryngol-Head Neck Surg 2010;53: 만현재까지내이에서의 항상성을위한많은연구와결과는보고되었지만 항상성에대한연구는많지않은실정이다. 이에본종설에서는내이의각각의구조의비감각성상피에서 항상성을유지하는기전을살펴보고그생리학적의의를살펴보고자한다. 와우의비감각성상피에서의 의이동은주로세포첨부의 ENaC(epithelial channel) 과비선택적양이온채널 (non-selective cation channel, NSCC) 로흡수되며, 세포기저부의, -ATPase 를통하여세포외측으로배출되는데, 이때기저부의, -ATPase는 을 배출하여첨부에서 흡수를위한원동력이된다. 첨부에서 의흡수를담당하는 ENaC 은 α, β, γ 세개의부단위 (subunit) 의조합으로구성되어있으며, 5) 최근에는또다른부단위인 δ가사람의뇌에서동정되기도하였다. 6) NSCC 는다양한종류가있는데, 세포내외의 Ca 2+ 농도나고리모양핵산 (cyclic nucleotide) 등의다양한신호에의해서대개 1가의양이온을흡수하며, 종류에따라 2가의양이온을흡수하기도한다. In situ hybridization 이나면역염색등의분자생물학적인연구에서는와우의각종상피세포에서 ENaC, /H + exchanger(nhe),, - ATPase and the - -2Cl - cotransporter(nkcc) 등의 흡수와연관된이온채널이나교환제, 수송로가존재한다고제기되었지만, 7-14) 이동이기능적인연구 Table 1. Fluid composition of the cochlear endolymph, perilymph, vestibular endolymph and the endolymph of endolymphatic sac 2) Cochlear perilymph Cochlear endolymph Vestibular endolymph Endolymph in the endolymphatic sac, mm , mm Cl -, mm HCO3 -, mm c Ca 2+, mm Protein, mg/d ,400 ph , -ATPase channel (inactive) 11β-HSD1 (active) GR Sgk1 [ ]>[ ] WNK4 Nedd4-2 [ ]<[ ] ENaC Fig. 1. Schematic drawing of glucocorticoid-regulated transport via ENaC in Reissner s membrane. ions in endolymphatic space are absorbed through apical ENaC and pumped out to the perilymphatic space through basolaterally located, -ATPase. Cytoplasmic ions, exchanged with ions through, -ATPase, are recycled to the perilymphatic space through basolaterally located channels. Inactive forms of glucocorticoid are activated by 11β-HSD1, which then increases ENaC expression via the glucocorticoid receptor-sgk1-nedd4-2 pathway. WNK4 was also suggested to be involved in the glucocorticoid regulated- transport pathway in Reissner s membrane. : glucocorticoid, GR: glucocorticoid receptor. 400

3 Transport via Inner Ear Nonsensory Epithelial Cells Kim SH, et al 로입증된곳은라이스너막 (Reissner s membrane) 과외구 (outer sulcus) 밖에는없다 ) 라이스너막은내림프공간과접하고있는라이스너막상피와외림프공간과접하고있는중피세포 (mesothelial cell) 의두겹으로이루어져있으며, 이중 의이동이입증된곳은라이스너막의상피이다. 라이스너막의상피에서의 의이동은주로모래쥐 (mongolian gerbil) 와마우스를이용하여증명되었는데, 15,17) 라이스너막의상피의첨부는내림프공간을향하고있고, α, β, γ 세개의부단위로형성된 ENaC 이존재하여 을흡수한다 (Fig. 1). 여기서 ENaC 은 α, β, γ 세개의부단위로구성이되어있지만정확히어떠한조합을이루고있는지는확실하지않다. 세포의기저부에는, -ATPase가 α 1, α 2, β 1, β 2 및 β 3 의동질이성체 (isoform) 의형태로존재하며이를통하여흡수된 이배출되고, 이흡수된다 (Fig. 1)., - ATPase 를통하여배출되는 과교환되어흡수된 은기저부의 채널을통하여다시세포외로배출되는데 (Fig. 1), 기저부에는 의배출을담당하는다양한 채널이존재함이증명되었으며, 모래쥐에서는 Kv1.5 채널이있음이기능적실험으로증명되었고, 마우스에서는 KCNJ10, KCNQ1, KCNQ3, KCNE2, KCNB1, KCNC3, KCNK1, KCNK2와 KCNK5 등의다양한채널이있음이역전사중 합효소연쇄반응 (RT-PCR) 에서나타났으며, 이채널들이각각부분적으로 의배출에관여함이기능적실험으로입증되었다. 와우에서는 +80 mv의와우내전위 (endocochlear potential) 가있으며, 라이스너막의기저부에는 채널과외림프와내림프의 농도차에의하여형성되는전위가 70 mv이므로라이스너막상피세포의첨부의양이온흡수를위한전기적원동력은 150 mv가형성되게되고, 세포내의 농도가, -ATPase에의해서 10 mm 로유지될때와우의 농도가 1 mm인것을고려하면화학적 이동의원동력은 60 mv이므로세포첨부를통한전체적인 이동의원동력은 90 mv(150-60= 90) 가된다. 이러한 +90 mv의원동력으로인해서 의흡수는라이스너막을통해서더강력하게일어날수있게된다. 외구에서의 의이동은모래쥐를이용한전기생리학적실험에서증명되었다. 16) 외구의상피세포의첨부에서는 Ca 2+ 에의해활성화되는 NSCC 을통하여 의흡수가일어나는데, 흡수된 은라이스너막과마찬가지로, -ATPase 에의해세포외로배출되고이때흡수된 은 Ca 2+ 의존성 채널 (Ca 2+ dependent maxi-k channel or small -K channel) 혹은 ATP 감수성 채널 (ATP-sensitive channel) 에의해세포내로재흡수된다 (Fig. 2). 하지만외구상피세포가차지하는면적이라이 ATP P2X2 NSC NSC channel, -ATPase Fig. 2. Schematic drawing of absorption via non-selective cation channel (NSC) in the cochlear outer sulcus cells. ions in endolymphatic space are absorbed through apical NSC channels and pumped out through basolaterally located, -ATPase. Cytoplasmic ions, exchanged with ions through, -ATPase, are recycled to the perilymphatic space through basolaterally located channels. Although the NSC system of the cochlear outer sulcus is also capable of absorbing, this relatively small epithelial domain is thought to primarily provide a parasensory shunt for efflux. P2X 2 receptors mediate stimulation of parasensory cation absorption by ATP via stimulation of the constitutive NSC channel and/or its own NSC permeability

Korean J Otorhinolaryngol-Head Neck Surg 2010;53:399-407 스너막의면적보다는적은부분이기때문에, 외구상피세포의 NSCC은 의흡수보다는주로 의흡수에관여하여, 와우내림프공간에서 의배출을일으켜과도한소음자극시에 을배출하는부경로로이용될것으로사료된다.

4 Korean J Otorhinolaryngol-Head Neck Surg 2010;53: 스너막의면적보다는적은부분이기때문에, 외구상피세포의 NSCC은 의흡수보다는주로 의흡수에관여하여, 와우내림프공간에서 의배출을일으켜과도한소음자극시에 을배출하는부경로로이용될것으로사료된다. 전정기관에서의 의이동도와우와유사하여 은세포첨부의 ENaC과 NSCC에의해서흡수되며, 세포기저부의, -ATPase 에의해서배출이된다. 와우와마찬가지로전정에서도분자생물학적으로는다양한부위에서 의흡수와연관된많은채널이나교환체, 수송체등이밝혀졌으나, 전기생리학적인연구에서그기능이밝혀진곳은전정전이세포 (vestibular transitional cell), 16) 반고리관의비감각성상피세포 (semicircular canal duct epithelial cell) 18,19) 및구형낭 (saccule) 의비감각성상피세포 20) 등밖에는없다. 내림프공간을접하고있는전정전이세포에서의 이동은모래쥐에서증명되었는데, 16) 이세포첨부의 NSCC 을통하여흡수되고, 세포기저부의, -ATPase에 의해서 과교환하여세포외로배출되며, 세포내로유입된 은 Ba 2+ (2 μm~1 mm), quinidine(1 mm), quinine(1 mm), Rb + (20 mm), Cs + (20 mm), NH + 4 (20 mm) 와 Tl + (0.5 mm) 등의억제제에의해서억제되는다양한 채널을통하여배출되게된다 (Fig. 3). 21) 이러한전정전이세포에서의 NSCC 의역할은와우의외구세포와마찬가지로 흡수보다는 배출을위한준감각통로 (parasensory shunt) 로작용할것으로사료되고있다. 반고리관의비감각성상피에서는 이동은배양된쥐의반고리관비감각성상피세포에서의실험을통하여규명되었다. 18,19) 은내림프측의상피세포첨부의 α, β, γ 의부단위로구성된 ENaC 을통하여흡수되며, 세포기저부의 α 1, α 3, β 1, β 3 등의, -ATPase 동질이성체를통하여 과교환되어배출되고흡수된 은 Kir2.1, Kir2.2, Kir2.3, Kir2.4, Kir3.1, Kir3.3, Kir4.1, Kir4.2, Kir5.1, Kir7.1 등의다양한 채널을통해배출된다 (Fig. 4). 이러한과정은와우의라이스너막과상당히유사한점이있는데, 반고리관의비감각성상피에서는상피세포의첨부에서형성되는전류가 이동을통한전류만이감지되는것이아니라라이스너막에는존재하지않는 cystic fibrosis conductance regulator(cftr) 를통한 Cl - ATP NSC P2X2 NSC channel, -ATPase S U ES Fig. 3. Schematic drawing of Na+ absorption via non-selective cation channel (NSC) in vestibular transitional cells. ions in the endolymphatic space are absorbed through apical NSC channels and pumped out through basolaterally located, -ATPase. Cytoplasmic ions, exchanged with ions through, -ATPase, are recycled through basolaterally located channels. Although the NSC system of the vestibular transitional cell area is also capable of absorbing, this relatively small epithelial domain is thought to primarily provide a parasensory shunt for efflux. P2X 2 receptors mediates stimulation of parasensory cation absorption by ATP via stimulation of the constitutive NSC channel and/or its own NSC permeability. S: sacule, U: utricle, ES: endolymphatic sac. 402

5 Transport via Inner Ear Nonsensory Epithelial Cells Kim SH, et al, -ATPase K+ channel (inactive) 11β-HSD1 (active) GR Sgk1 Nedd4-2 S ENaC U ES Fig. 4. Schematic drawing of glucocorticoid-regulated transport via ENaC in semicircular canal epithelial cells. ions in the endolymphatic space are absorbed through apical ENaC and pumped out to perilymphatic space through basolaterally located, -ATPase. Cytoplasmic ions, exchanged with ions through, -ATPase, are recycled to the perilymphatic space through basolaterally located channels (Kir channels). Inactive forms of glucocorticoid are activated by 11β-HSD1, which then increases ENaC expression via the glucocorticoid receptor-sgk1-nedd4-2 pathway. : glucocorticoid, GR: glucocorticoid receptor, S: sacule, U: utricle, ES: endolymphatic sac. 흡수전류도같이감지된다는점이라이스너막과의차이점이다. 구형낭에서의 이동의통로는최근에마우스를이용한전기생리학적실험에서규명되었는데, 구형낭의천정부위를이루고있는비감각성상피에서 이흡수됨이밝혀졌다. 20) 구형낭비감각성상피에서의 의이동은구형낭의인접기관인와우의라이스너막에서의 이동과매우유사하다. 내림프의 은구형낭비감각성상피세포의첨부에위치한 ENaC 을통하여흡수되어기저부의, -ATPase 를통하여 과교환되어외림프공간으로배출되고, 이때흡수된 은기저부의 K ATP, K Ca 혹은일부산성민감성을보이는 K 2P 채널 (some acid-sensitive K 2P channels such as KCNK1, KCNK3, KCNK5, KCNK9 and KCNK17) 과 NSCC 및 KCC(, Cl - cotransporter) 를통하여배출될것으로생각된다 (Fig. 5). 내림프낭을통한 의이동은와우나전정에비해더욱활발할것으로생각되는데, 이는내림프낭의내림프액이와우와전정과는달리 이높고 이낮은조성을가 지고있기때문이다. 2) 대개물의이동은 의이동에따라서이차적으로일어나므로, 생리학적으로나특정내이질환에서내림프낭이내이액의전체부피를결정하는데중요한역할을할것으로생각된다. 내림프낭의상피세포는크게두가지로나뉘어진다. 한가지는미토콘드리아 (mitochondria) 가풍부한세포이고, 다른한종류는리보솜 (ribosome) 이풍부한세포인데, 22) 미토콘드리아가많은세포가이온의흡수와내이액의항상성조절에중요한역할을할것이라사료된다. 현재까지전기생리학적으로기능이밝혀진내림프낭의상피세포에서 이동에관여하는채널, 교환체및수송체는아밀로라이드에낮은친화력을가지는 채널 (low-amiloride-affinity channels) 23) 및 NSCC, 24) ENaC, 25) NHE( -H + exchanger), 26), -ATPase, 27) 지연성정류 채널 (delayed rectifier channel) 28) 등이다. 이들중아밀로라이드에낮은친화력을가지는 채널및 NSCC, ENaC, NHE 등은세포의첨부에위치하여내림프액으로부터 을흡수하는데 (Fig. 6), 사람의내림프낭에서는 α, β, γ ENaC 과 NHE 1,2 의존재및기능이규명되었고 (NHE1<<NHE2), 25,26) 낮은친화력을가지는 채널및 NSCC 는기니아픽 (guinea pig) 을이용한실험에서그존재및기능이증명되었다. 23,24) 세포내 403

6 Korean J Otorhinolaryngol-Head Neck Surg 2010;53: GR channel, -ATPase S dr U ES Fig. 5. Model of absorption by saccule extramacular epithelium. The saccule (S) is bounded by an epithelial monolayer with one tubular connection that bifurcates to the endolymphatic sac (ES) and utricle (U) and another tubular connection to the cochlea via the ductus reuniens (dr). from endolymph moves into the cells through -permeable channels in the apical membrane. This pathway has the pharmacological fingerprint of ENaC, but may include other channels. exits the cell at the basolateral membrane by active extrusion via the -pump,, -ATPase. brought into the cell on the -pump leaves the cell across the same membrane by electrodiffusion via -permeable channels. The rate of absorption is stimulated by activation of glucocorticoid receptors (GR). Candidate isoforms of the transporters are discussed in the text. : glucocorticoid. Apical ATP P2Y LAASC ENaC NSCC H + NHE1,2 Delayed rectifier channel, -ATPase S U Basolateral ES Fig. 6. Schematic drawing of transport in endolymphatic sac epithelium. ions in the endolymphatic fluid are absorbed via apical non-selective cation channels (NSCC), low-amiloride affinity channels (LAASC), ENaC and NHE 1,2 (2>>1). The absorbed is pumped out through basolaterally located, -ATPase. Cytoplasmic ions, exchanged with ions through, -ATPase, are recycled through basolaterally located delayed rectifying channels. A P2Y receptor in the apical membrane regulates stimulation of absorption by ATP. All depicted processes are modeled here in one cell but may occur in multiple cell types. S: sacule, U: utricle, ES: endolymphatic sac. 404

7 Transport via Inner Ear Nonsensory Epithelial Cells Kim SH, et al 로들어온 은기저부의, -ATPase에의하여 과교환되어배출되며, 27) 이때들어온 은기저부의지연성정류 채널을통하여배출되는것이기니아픽에서증명되었다 (Fig. 6). 28) 기니아픽에서, -ATPase 를억제제인 ouabain(1 mm) 을사용하여차단하였을때세포외로 이배출되지못하여세포내 농도가증가하는것이관찰되었는데, 이는주로미토콘드리아가많은세포에서일어나는것이밝혀졌고, 이는, -ATPase가에너지를소모하기때문에미토콘드리아활동이활발한세포에서많이일어날것이라고생각할수있다. 27) 현재까지내이에서의 흡수를조절하는주요물질로는부신피질호르몬과 ATP 가밝혀졌다. 합성부신피질호르몬인덱사메타손 (dexamethasone, 100 nm) 은마우스라이스너막, 15) 배양된쥐의반고리관의비 감각성상피 18,19) 및마우스구형낭의비감각성상피 20) 에서 의흡수를증가시킴을전기생리학적실험을통해규명되었다. 덱사메타손은마우스라이스너막, 배양된쥐의반고리관의비감각성상피에서 11β-HSD1 에의해서비활성화형에서활성화형으로전환되며, 부신피질호르몬수용체를통하여작용한다 (Figs. 1 and 4). 부신피질호르몬수용체에의하여흡수된덱사메타손은 SGK1 을통해 Nedd 4-2를인산화 (phosphorylation) 시키고, ENaC에유비퀴틴 (ubiquitin) 으로작용하던 Nedd 4-2는 phosphorylation이되어탈유비퀴틴화 (deubiquitination) 되면서 ENaC의발현이저하되는것을방지하거나, 발현을증가시켜 ENaC 을활성화시키게되고, 이에따라 의흡수가증가하게된다. 또한마우스라이스너막에서는활성화된부신피질호르몬은부신피질호르몬수용체를거쳐 SGK1을증가시켜세린-트레오닌단백활성효소 (serine-threonine protein kinase) 의일종인 WNK4 를인산화시키고, 활성화된 WNL4 가 ENaC 을활성화하여 흡수를증가시키는다른경로도존재할수있다 (Fig. 1). 의흡수가증가함에따라상대적으로, -ATPase와 채널의발현이나기능도증가하게된다. 마우스구형낭에덱사메타손이부신피질호른몬수용체를통하여 흡수를증가시키는것은전기생리학적인기능적실험으로는증명되었지만 (Fig. 5), 어떠한경로를거치는지는분자생물학적으로는아직밝혀지지않았다. ATP는퓨린계수용체 (purinergic receptor) 인 P2 수용체를통하여 의흡수를조절한다. P2 수용체는퓨린 계물질과수용체간의리간드 (ligand) 에의해서상대물질의활성화가조절되는 P2X 수용체와 G 단백수용체 (G proteincoupled receptor) 를통하여조절되는 P2Y 수용체두종류가있는데, 지금까지 7개의 P2X 수용체와 (P2X 1-7 ), 5개의 P2Y 수용체가 (P2Y 1,2,4,6,11 ) 존재함이규명되었다. 29) 모래쥐의와우외구와전정전이세포에서는 ATP가 P2X 수용체를통하여양이온의흡수를증가시킴이확인되었으며 (Figs. 2 and 3), 16) 이는앞에서도언급한바와같이주로소음등의외부스트레스시에 ATP 를증가시켜 흡수를활성화시켜내이의보호기전으로작용할것으로사료된다. 모래쥐의내임파낭상피세포에서도 ATP 는 NSCC 을통한양이온의흡수를증가시키는데, 이는 P2Y 수용체를통하여일어나는것으로규명되었다 (Fig. 6). 30) 이외에도염증성사이토가인 (cytokine) 인 INF-γ(50 nm for 24 hrs) 와 IL-1β(10 ng/ml for 24 hrs) 가내림프낭상피세포의 NHE1, 2와 ENaC 을통한 의흡수를저하시키는것으로밝혀졌다. 26) 내임파액의 농도는정상적인청각과평형을유지하기위해서는낮게유지되어야한다. 앞에서도이미언급한바와같이와우와전정, 내임파낭상피세포의 ENaC, NSCC 은 의이동에중요한역할을하며, ENaC 은내임파낭에서더욱중요한역할을할것으로사료되며, NSCC 은와우외구와전정전이세포에서소음성스트레스등에대한내이보호기전으로작용할것으로사료된다. 최근내이상피세포에서이온채널의이상이내림프수종 (endolymphatic hydrops) 를일으키는원인이될수있다고제기되었으며, 31) 몇몇연구에서는내림프액에서의 흡수의저하가내림프수종과연관이있다고보고되었다. 32,33) 또한내이의면역반응시에염증성사이토카인인 INF-γ 와 IL-1β 가증가된다고보고되었는데, 34,35) 이러한면역반응물질의증가는 의흡수를저하하고, 이는자가면역성내이질환과내림프수종이연관성이있을수도있음을간접적으로시사한다. 부신피질호르몬제제는여러연구에서제시된바와같이메니에르병이나돌발성난청의치료제로이용되고있는데, 36) 이는앞에서제시한연구결과에서나타났듯이특정내림프수종상황에서증가된 의흡수를라이스너막, 반고리관비감각성상피및구형낭비감각성상피등을통해증가시켜내림프수종을경감시켜현훈이나난청증상을호전시킬수도있을것이라사료된다

8 Korean J Otorhinolaryngol-Head Neck Surg 2010;53: 현재까지 ENaC 이나다른 흡수이상이난청과연관이있다는보고는없다. 하지만와우혈관조와지지세포, 나선신경절에존재하는 TMPRSS3(a transmembrane serine protease) 의유전자변이의경우비증후군성상염색체열성난청 (DFNA8/10) 을초래하는것으로규명되었는데, 37) 이 TMPRSS3 는자가촉매적단백분해기전에의하여 ENaC 을활성화시키는것으로알려져있어 ENaC 이선천성난청과도연관이있을수있음을시사한다. 내이에서의 이동은대부분비감각성상피세포에의해서일어나며, 이러한 의이동은내림프의 농도를낮게유지하여청각과평형을유지하게하는데필수적이다. 또한내이에서의 의이동은수분의이동과밀접한연관이있으리라사료된다. 의이동은대부분내림프공간에서외림프공간쪽으로일어나며, 내림프낭을제외하고는내림프공간에서의 의농도는낮기때문에평상시이들의역할은제한적일수있으나, 메니에르병이나전정도수관확장증등의내림프수종이동반된경우나특정병적상황에서 의농도가일부라도증가해있는상황에서는내이에서 의이동이내림프액의부피의조절에중요한역할을할수있을것이다. REFERENCES 1) Couloigner V, Sterkers O, Ferrary E. What s new in ion transports in the cochlea? Pflugers Archiv-European Journal of Physiology 2006; 453(1): ) Marcus DC, Wangemann P. Cochlear and vestibular function and dysfunction. In: Alvarez-Leefmans FJ, Delpire E, editors. Physiology and pathology of chloride transporters and channels in the nervous systemfrom molecules to diseases. 1 st ed. Boston: Elsevier/Academic Press; p ) Moser T, Brandt A, Lysakowski A. Hair cell ribbon synapses. Cell Tissue Res 2006;326(2): ) Jørgensen F, Kroese AB. Ionic selectivity of the mechano-electrical transduction channels in the hair cells of the frog sacculus. Acta Physiol Scand 1994;151(1): ) Kosari F, Sheng S, Li J, Mak DO, Foskett JK, Kleyman TR. Subunit stoichiometry of the epithelial sodium channel. J Biol Chem 1998; 273(22): ) Waldmann R, Champigny G, Bassilana F, Voilley N, Lazdunski M. Molecular cloning and functional expression of a novel amiloridesensitive channel. J Biol Chem 1995;270(46): ) Bond BR, Ng LL, Schulte BA. Identification of mrna transcripts and immunohistochemical localization of Na/H exchanger isoforms in gerbil inner ear. Hear Res 1998;123(1-2):1-9. 8) Couloigner V, Fay M, Djelidi S, Farman N, Escoubet B, Runembert I, et al. Location and function of the epithelial Na channel in the cochlea. Am J Physiol Renal Physiol 2001;280(2):F ) Crouch JJ, Sakaguchi N, Lytle C, Schulte BA. Immunohistochemical localization of the Na-K-Cl co-transporter (NKCC1) in the gerbil inner ear. J Histochem Cytochem 1997;45(6): ) Erichsen S, Zuo J, Curtis L, Rarey K, Hultcrantz M. Na, K-ATPase alpha- and beta-isoforms in the developing cochlea of the mouse. Hearing Research 1996;100(1-2): ) Goto S, Oshima T, Ikeda K, Takasaka T. Expression and localization of the -H + exchanger in the guinea pig cochlea. Hearing Research 1999;128(1-2): ) Grunder S, Muller A, Ruppersberg JP. Developmental and cellular expression pattern of epithelial sodium channel alpha, beta and gamma subunits in the inner ear of the rat. Eur J Neurosci 2001;13(4): ) McGuirt JP, Schulte BA. Distribution of immunoreactive alpha- and beta-subunit isoforms of Na,K-ATPase in the gerbil inner ear. J Histochem Cytochem 1994;42(7): ) Zhong SX, Liu ZH. Immunohistochemical localization of the epithelial sodium channel in the rat inner ear. Hear Res 2004;193(1-2): ) Kim SH, Kim KX, Raveendran NN, Wu T, Pondugula SR, Marcus DC. Regulation of ENaC-mediated sodium transport by glucocorticoids in Reissner s membrane epithelium. Am J Physiol Cell Physiol 2009;296(3):C ) Lee JH, Chiba T, Marcus DC. P2X2 receptor mediates stimulation of parasensory cation absorption by cochlear outer sulcus cells and vestibular transitional cells. J Neurosci 2001;21(23): ) Lee JH, Marcus DC. Endolymphatic sodium homeostasis by Reissner s membrane. Neuroscience 2003;119(1): ) Pondugula SR, Raveendran NN, Ergonul Z, Deng Y, Chen J, Sanneman JD, et al. Glucocorticoid regulation of genes in the amiloridesensitive sodium transport pathway by semicircular canal duct epithelium of neonatal rat. Physiol Genomics 2006;24(2): ) Pondugula SR, Sanneman JD, Wangemann P, Milhaud PG, Marcus DC. Glucocorticoids stimulate cation absorption by semicircular canal duct epithelium via epithelial sodium channel. American Journal of Physiology-Renal Physiology 2004;286(6):F1127-F35. 20) Kim SH, Marcus DC. Endolymphatic sodium homeostasis by extramacular epithelium of the saccule. Journal of Neuroscience. In press ) Wangemann P, Marcus DC. Membrane potential measurements of transitional cells from the crista ampullaris of the gerbil. Effects of barium, quinidine, quinine, tetraethylammonium, cesium, ammonium, thallium and ouabain. Pflugers Arch 1989;414(6): ) Peters TA, Tonnaer EL, Kuijpers W, Cremers CW, Curfs JH. Differences in endolymphatic sac mitochondria-rich cells indicate specific functions. Laryngoscope 2002;112(3): ) Mori N, Wu D. Low-amiloride-affinity channel in the epithelial cells isolated from the endolymphatic sac of guinea-pigs. Pflugers Arch 1996;433(1-2): ) Miyashita T, Tatsumi H, Furuta H, Mori N, Sokabe M. Calciumsensitive nonselective cation channel identified in the epithelial cells isolated from the endolymphatic sac of guinea pigs. J Membr Biol 2001;182(2): ) Kim SH, Park HY, Choi HS, Chung HP, Choi JY. Functional and molecular expression of epithelial sodium channels in cultured human endolymphatic sac epithelial cells. Otol Neurotol 2009;30(4): ) Son EJ, Moon IS, Kim SH, Kim SJ, Choi JY. Interferon-gamma suppresses -H + exchanger in cultured human endolymphatic sac epithelial cells. J Cell Biochem 2009;107(5): ) Miyashita T, Tatsumi H, Hayakawa K, Mori N, Sokabe M. Large Na(+) influx and high Na(+), K(+)-ATPase activity in mitochondria-rich epithelial cells of the inner ear endolymphatic sac. Pflugers Arch 2007;453(6): ) Wu D, Mori N. Outward current in epithelial cells isolated from intermediate portion of endolymphatic sac of guinea pigs. Am J Physiol 1996;271(5 Pt 1):C ) Lee JH, Marcus DC. Purinergic signaling in the inner ear. Hear Res 2008;235(1-2):

9 Transport via Inner Ear Nonsensory Epithelial Cells Kim SH, et al 30) Wu D, Mori N. Extracellular ATP-induced inward current in isolated epithelial cells of the endolymphatic sac. Biochim Biophys Acta 1999; 1419(1): ) Gates P. Hypothesis: could Meniere s disease be a channelopathy? Internal Medicine Journal 2005;35(8): ) Morgenstern C, Mori N, Amano H. Pathogenesis of experimental endolymphatic hydrops. Acta Otolaryngol Suppl 1984;406: ) Silverstein H, Takeda T. Endolymphatic sac obstruction. Biochemical studies. Ann Otol Rhinol Laryngol 1977;86(4 Pt 1): ) Pawankar R, Tomiyama S, Ikezono T, Nonaka M, Jinnouchi K, Yagi T. Interferon-gamma expression in the inner ear of rats following secondary immune reaction in the endolymphatic sac. Acta Oto-Laryngologica 2004;124(553): ) Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM. Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation. Jaro-Journal of the Association for Research in Otolaryngology 2003;4(2): ) Barrs DM, Keyser JS, Stallworth C, McElveen JT Jr. Intratympanic steroid injections for intractable Meniere s disease. Laryngoscope 2001;111(12): ) Guipponi M, Vuagniaux G, Wattenhofer M, Shibuya K, Vazquez M, Dougherty L, et al. The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Hum Mol Genet 2002;11(23):

untitled

untitled Research in Vestibular Science Vol. 16, No. 1, March 2017 Review pissn 2092-8882, eissn 2093-5501 https://doi.org/10.21790/rvs.2017.16.1.1 메니에르병병인기전의전기생리학적연구 연세대학교의과대학이비인후과학교실 김성헌 Ménièreʼs Disease and