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rigts reeed

SRUCURE AN FUNCONOF VOLAGE-GAE ONCHANNEL

William CaerallDeparment of Pharmacology, 130 University of Washingon, eale,

Wahngon

Y WORDS: on channel, acion tential eectrical exctabiity ion transr membraneproens

CONNS

INTRODUCTON . . 494

STRUCTURE AND FUNCTON OF SODUM CHANNEL SUBUNTS . 495Purcaton an Characterzaton. , 495Conn an Pma Stcture of the Soum Channe Subunt. 496Conn an Prma Structure of the { n {2 Subunt. 498Functona Roe of Na+ Channe Subunt .. . . . . .. . . . .. . . . . 5Mchanm of Acton of Subunt . . .. . . . . . .. 50

STRUCTURE AND FUNCTON O CALCUM CHANNEL SUBUNTS. . ..... . . . 502Moecuar Propee of the Subunt of Skeeta-Mue Cacum Channe .. . 502Subunt of Pure Carac Cacum Channe ... .. ... . . . .. .. . .. . 5Subunt of Pure Neurona Cacum Channe . . . . .. . . ..... ... . . . .. ..... . 5Mutpe lofo of the Subunt of Cacum Channe . .. .. . . . . . .. . .. .. . 505uncto Roe of Cacum Channe ubunit . . .. .. .. . . . . . . .. . 5

Mchnm of Reuaton by { Subunt . , . , .. , , , . , , , , , , , , , 50NTERATON OF CALCUM CHANNELS WTH NTRACELLULAR EFFEOR

PROENS , , , . . , , , , ... , , . , , . , . , , , , , , . , 50CacumReeae Channe .. .. . . . .. . ... .. . . . .. . .. . .. . .. . .. . . . .. ... . 50Snaptc Membrane Proten . .... .. . . ... ... .. . .. .. ... 50

STRUCTURE AND FUNCTON OF K+ CHANNEL SUUNTS.... 50Prncpa Subunt of Channe. . .. .. . . . . .. . ... .. . . .. . .. . . . . 510Subunt ComOton of Pure Neurona K+ Channe , .. .. . .. . . ... . ... 510Moeuar Properte of an Aa Subunt of a Channe. . . .. .. . . 512

STRUCTRAL ASS FOR ON CHANNEL UNCTON .. . . . .. . .. .. . . .. .. . 512

VOLTAGE-DEPENDENT ACTVATON ....... 51

ON CONDUCTANCE... 5The Etraceuar Mouth of the Pore .... . . . .... . .. ... .. .... . . . ...... 51he Intraceuar Mouth of the Pore . " .. , , .. , .. 8 Sctv, , , , , , , , , , , , . , , , , , , , , , , . , , , , , , 520

NACTV ATON... .. . .. .. 22

00454/5/070043$0000

Ann

u.Rev.Biochem.1995.64:49353

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AERA

F vn fom nnl .. . 22A ngedd Mode of odum hanne Fa naciaon 525naciaion of Poaium Channe 525

BSRACVltaggad in channl a pnible f gneain f lctical ignal cell ees. Te c suuts e ees f gee fly dc fuc s vgeged cels y eselves hey exessd ssc e e uxy suuts c icese fucilexpes nd dfy the fucnal pptis f pincipal ubunit.Suctual lnt that a qud f vltagdpndnt activatn lctiv cducnce, d cv v be denid, nd h canss

f ci e eg exed hug ugeess, exess eelgusces d fucl ss ese xpees evel t s fly fchanne but up c tucua h wit vaiatns apppiatef fuctl spciztn f each cnl typ

NOCON

e vtgeged sdu, clcu d pssu chels e espsilef he gee f cducted ectc gals n us nd he excble

clls. h peey cs esulg f civt f the chal isic Up dez, eeity t sdiu, ccu, pssuincas daaclly ve peid f 05 hundd f sec and thndeceass t the asine vl ve a peid f 2 sc t fw scnd hisps ev esus f expeety sepbe gg pcessestha c n cl fucn: ctiv, which cn th ate advge depedee f e ee cese flg dep, dcv c ctls th te d vtg dpndc f h uquntu f he pemelty he eing lv duing a aintaid dplza h vltggatd n cnl can tf xi in t functy dsnc stes gups f stes: estng, civ, ad inactvd Bhesig d cved ses e cducg, u ces ve eeved pged deplzt e efcy uess e ce is epzed t l t u t te esig stt e cducce f eacvd in chaels i bh hghly lctiv ad aaly cin Slcvy ng h physigca n ng f fld f dum channl ve OOOfd f clcu cels d ll ee clsses f ces

cduct s css gcl ees t es pcg t te ffee dffus ug su. desdg e ecu ses f vgedpede ctvtn, pd iacvain, and slctv and fcn ncducce s j g f cut sch hes cicl sglges.

Annu.Rev.Biochem.1995.64:493531

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VOTAGE-GATED O HAE 495

STRUCTURE AND FUNCTION OF SODIUM CHANNEL

B

hez

The na eenaon of he bn ce of he a ban Na channeoo avanae of neroon ha b wh hh afn a ecc ohe channe coex an h co b e a oeca obe o enf oen coonen e o of neooxn ha ac a ffeen eceoe on e Na channe hae been ecbe 13 Be e 1 bneoooxn axoxn an -conooxn whch block on concance Se 2

b he on baachooxn eane aanooxn an aconne eln n een acaon of he Na+ channe Se 3 bn he olee-coon oxn an ea aneone on whch ow o block nacaonen whch bnd a h e ao enhance he een acvaon of he Nacannl ca by txn acn a neroon receor e . eceor e 4bn a econ cla of coon on (-coon on ha h he voaeeenence of acvaon o ore neave ebane oena who ofn Na+ channel nacaon Fna eceo e 5 bn he beeoxnan cguan agn a cau nerona rn h e e

deenence of Na+ channel acvaon an block Na+ channe nacvaonrc cmca ncan o he 60 bn an he 6

bn of he a ban o channel n wa accolhe b ecfccoalen abeln of neuoxn eceo e 3 a on he Na channecolex wh hooeace eae of - an -copon oxn eecvel (6. earaon of wo hooeacve ervave of an -coon oxnby ncang cmagay a c ang ac uun

(7). aaon nacvaon e wee alo e o obe he oeca eofhe bn of he Na+ channel. Meaeen of he ae ze fo nacvaon of ehe eoooxn o copon oxn bnn o he Na+ channefro ra bran or eel elecrol a a rcre of 30 8). In cona aaon nacvaon e of corpon oxn bnn acv of a ban o channel lcae wo olee of 266 D an45 D conen wh a oe of boh an bn n foaon ofneooxn eceo e 4 (0

The o channe fro eecc ee elecola wa fe n hebnn of aolabele eoooxn a a ecc aa (1). I cone of a

nle olee of 80 D a n ze o he bn of he a brano channel (12) wh a hh ee of Nnke cabohae (3)Pcaon of e nac o channe fo a ban n hh an

bnn of axoxn a an aa reeae a coex of one bn of 260D an w nc bn w an aaren olecla a of 6 D




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49 ARA

and 2 with an apparent molecular mass of 33 (117) The 2 subunit iscovalently attached to the ( subunt by isulfde linkage while the subunits noncovalently associated. The subunit stochiometry of 1: : 1 ieled amolecular weiht ( D) in close areement with that of the solubiliedoiomeic channel (316 ) (8) aial proteoltc maps showe ha the an 2 subunits were distnct and probabl unrelate (17) oth the an2 subunts were covalentl labeled by a hdrophobic probe specifc fortransmembrane segments of protens in mxed micelles of Triton X-OO andphosphatidlcholine or in reconstituted phosphatidylcholine vesicles and bothsubunits were preferentall extracte into the nonionic eterent Titon Xin a phase separation procedure as expecte for ntrnsc membrane protens

(1) The subunits and both subunits are heavil lcoslate (17 20).The apparent molecular weights of the eglcosated subunits were etermine to be 220 23 and 21 for 1 n 2 respectiel whichsuggests that a substantal fraction of the mass of the native subunits s carbhrate and that much of the proten mass s exposed on the extracellularsurface (1) hese experments led to a heterotrimeric model for the subunitstructure of the brain sodium channel as illustrated in Figure A

he Na channel from rat and rabbt skeletal muscle sarcolemma contansa large ( subunt of kD and a small subunt of approxmately kD

(2123) Enymatic decoslation of the puried subunit ieded a corepeptide of 26 D. Althouh the 38 k subunit of the Na channel could beresolve into a doblet of7 kD an 39 D stoichiometric analsis suggestedthat there s ony a sngle subunt assocate noncovaenty wth each large( subunt he noncovalent assocaton mples that the subunt n purfedskeletal muscle sodum channels s -like Studes using affnty-purifedpol clonal antiboies to the purifed rat brain subunit identife immunoreactve -like subunits in rat skeletal muscle that appeared as a closely spaced

oublet of 1 an 38 kD on SDS-AGE consistent with he results obtaineusng pured soum channels

Cg d m Se e Sdm Ce Subunit

Clonng of the subunit of the soum channel from eel electroplax by NodaNuma and colleaues (2) gave the initial insht into the primar structureof a voltae-ated ion channel Usin olionucleotides encodin short segments of the electric eel electroplax soium channel an antiboies irecte

)Fgue uu sruures f he vlgeged hes The geme d hemreres f suus f he lgeged hels e llusred. se f rle nkedglsln; se f AMdendn n hshln SS nesuun dsulded



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B

y

VO-D ON CHNN 49

Annu.Rev.Bioche

m.1995.64:493531.Downlo

adedfromwww.annualreview

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CAEA

in i, No e (2) ioe cN encoin he enie popepiero expreion irrie o eecroplx N The deduced ino cideuence evee poein wih ou inell hoooou domin echconinin mipe poeni ph-heic nene emen (Fiue2). he weh o inorion conined in hi deduce prir rucueh revouionie eerch on he vogege ion chnne

e cDN encoing he eecropx odiu chnne wee ue o oeDN encodin ree diinc u hih hooloou r rin odiuchnne (pe I, II, n III) (26, 27). cN encoin he leive picepe II oium chnne wee ioe inepnen ceenin expeionlirie wih nioie gin he in odiu chnne uuni (28,

29). he pe II ene conin wo jcen exon encoin egmen I (0)h e eive pce ino mue mN in eveopmen euenne he pe II i mo pominen in emonic n neonl in whilehe ype II or i o proinen in he u rin (0 1) cNencodin he pe II/II odium chnne wee ue poe o ioe cNencodn odu cnnel uun expree n ele ucle nd er owrngency hriiion (2) The odiu hnne uuni iexpeed pii in dul kele uce (2); he h odium chnne uuni i expreed prril in he nd o in uninnerved o deneve

ele ule 4 ee diu hnnel ve cle rucur reionhip o he hee rin odiu chnne uuni In enerl he iiln no cd equence ree n he ooloou don ro rnmerne een ough while he ineu connecin oop e nohih conerved.

opeen DN encodn uuni o ree dinc odiu chnne r D hve een coned cro-hriion, n o ohe prm ucure o he coeponin oiu chnnel hve een deuce (). hu i ppe h D o h mulipe oiuhnne gene oerve in r reuy hee diinc gene hve iinroe in elecic exciii in oh pecie.

Moe ecen, new puive oiu chnne uun hve een coneo gil n her DN lirrie (8 9). The ino i equence einhe ou-oin ucure o he ohe uuni n n o hei oheconeve eue, u e inc ore veren n e oe uunprevuy rered h een ugeed ee ne li/herdu chnnel deine new ui o oiu chnne

lonng nd P Stuctu of th {I nd {2 SubunitsDN cone encoding he uuni o he r in N chnnel wereiled un conon o polere cn recon nd rr-creen enue ed n e ino ci euence o he ino erinu o e



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!,"

-O

l

B ci+ 1

K+

VOA-AD ON CHANN

V H

OUS

DEco co

Tranmembrane orgaizaio o he ion channel ubui. T prima rucue bn of he voage-gaed o aes are raed Cyder repeet pobabe p e

emen eeen he oede o eah bn wh eh oxeooona o h nbe o ano ad ede ' e o pobabe Nked oyon; e o deoaed oen hohoon

Annu.

Rev.Biochem.1995.64:493531



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500 CAEA

pured proten 40 The deduced prmary tructure ndcate that the uunt a 22,85-dalton proten that contan a mall cytoplamc doman,a ngle putatve tranmembrane egment, and a large extracellular doman

th four potental N-lnked glycoylaton te Fgure A, content thprevou bochemcal data , 9 Northe blot analy revealed a 4nucleotde mNA n rat ran, heart, and pna cord, and at lo level n ateletal mucle.

A mlar approach a taken to clonng the P ubunt t alo ha a ngletranmembrane egment a mall ntracellular carboxyl termnal doman anda large glycoylated extracellular amnotermnal doman unpublhed reult)

F e N+ he bEarly ochemal experent ponted to a domnant functonal role or the uunt ovalent laelng and radatonnactvaton tude mplcated uun fomaon of he ecepo e fo eodooxn and axoxn e1 ) and both and -scoion toxins te and 4) 4 5 ) n addtona channel pured from eel electroplax and chcen heart contaned only uunt ut retaned gh anty for tetrodotoxn and, n the cae of eelelectroplax, onconductance actvty , 4, 4) Becaue tetrodotoxn and

axtoxn are thought to lock the pore of the Na channel and the corpontoxn affect actvaton and nactvaton gatng thee ochemcal reult uggeted that uunt ere nvolved n oth on conductance and gatng.

otental functonal role of the P and P ubunt ere analyzed n puredand reconttuted odum cannel preparaton. Selectve removal of the uunt from the complex of detergent-olulzed or reconttuted ratbran Na channel reulted n the complete lo of Jaxtoxn-bndngactvty, veratdneactvated Na nux, -copon toxn bndng actvty,and voltage-actvated on conductance 4, 44) Tetrodotoxn uanttatvely

talzed the olulzed complex agant the lo of the ubunt and loof functonal actvte n contrat, removal of the unt by reduton ofdulde bond yelded a preparaton of l that retaned a channel functon. hee tude hoed that a complex of and P ubunt bothneceary and ucent for channel functon n the pured tate and uggetedthat uunt, but not uunt, are requred to talze the functonaltate of pufed bran odum channel n detergent oluton

Te role of the and uunt Na cannel functon n an ntact cella teted drectl thouh expreon of the and ubunt n Xoocyte RN encodng uunt from ran, keletal mucle, and heart alonei ufient to enode funtionl N hnnel in n ooyte , ,, 5 Hoever, ter nactvaton lo relatve to that oerved nneuron or keletal mucle, and ther voltage dependence of nactvaton




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VOLTAGE-GATED ION CHANNELS 501

he to oe ote ebae oteta 9 9- Co-eeo olow-moleular-weght RNA rom rat bran or skeletal musle aelerates n

ataton hts the oltage epenene o nataton to more negatemembrane potentals an nreaes the peak ampltue o Na uent exprese rom lone e ubunts (29 32 50 5. These results suggeste aobe roe or the owoeuarweght a/or ubut Na+hannel unton oexpreson o type A e ubuts an subunt n ooytes resulte n a 2.5ol nreae n the ampltue o the peakNa urrent an nreae n the rate o ataton a 5ol aeleraton n therate o nataton an a 9 mV sht n the hyperpolarng reton o steaytate at nataton 0 5 Coexpreon o rat or huan ubunt wth

the rat skeletal musle e subunt or rat bran type e subunts n ooye gae r reu -4Na hannel subunt hae also been expresse both staby an transently

n mammalan ells n uture 5557. Stable lnes o Chnese hamter oaryell expresng only the type A rat bran Na hannel subunt generateNa+ urent wth a nomal tme oure 55 5 n spte o the lak o lubunt etetabe by Nothe bot Wete bot an atty aay nen ooyte 5. oweer the lee o untonal Na + hannel expresson thee el lne low relate to RNA leel Co-expreo o ubuntswh tye A e subunts n mammalan ell lne result an nrease n thepeak Na urrent an the total number o Na+ hannels etete by saxtoxnbng a wel a a ht the oltage eenee o ataton a nataton 5). Thu ubunts n aalan ell may stable the Na+hannel oplex n the pasma embrane whh reults nreae untona expresson an also may alter the oltage epeene o hannel gatng.Atoal experments are neee to are whether aoaton o erentl ubut wth ubut a oy the uto o the ubut.

Mechanism of Action of { Subunits subunt hae mltle eets on soum hannel untonnreae peakurent aelerate ataton an nataton an altere oltage epeneneo ataton. Thee ultple eet ay reult ro tt oleularnteratons between e an l ubunts or rom a ngle moleular mehansmthat alter mutle apets o oum-hannel unton. Clone skeletal mulesoum hannel e ubunts an type A an bran soum hannel e ubuntexpresse n ooytes exhbt two promnent gatng moe a rap moe

whh atato olete a ew leo a a low gatng oen whh nataton s slow an sngle soum hannels open repeately ungog eoaato 9 60 he ees o subuns on the tme oureo ataton an nataton an posbly eets on the oltage epenene onataton aear to reult rom a ht rom he ow o the ap gatng oe



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R

nduced y oexsson o th suunt 4) Thus a snge moecuanteacton th th 1 suunt may sucnt to chang th ngt

atonshp tn ths to gatng mods of e

suunts and aus a shftof sodum hanns to th apd gatng od. Ts shf n gatng mod oudaect the mute aspets o sodum channe uncton that de eteen the tountonay dstnt modes o gatng.

AN NN ALM HANNEL

BN

p h b km h

Th caum hannes n the tansvse tuu mmans o skta mushave sved as a mary ohemca and moua mode o studes ocacum channs ecaus of th aundance. These channes seve to ctcaphysoogca oes. e oth acum channes they medate cacum entyn sponse o depoaaon ove h votagegated caum hannes nskta mus atvat vry soy and aum ntng vrat sk-eta musce though votagegated cacum channs s not equed o muse

conaton. t apeas to sv to ensh ceua cacum duing peiods oapd atvty and to ncease ntaceua cacum n spons to tetanc stm-uaton hh ads to nasd ontat oc. Th pmary physoogao fo th skta mus aum hann s to srv as a votag snso nextatonontaton oung Votaggated cacum channes n th tans-vs tuu memanes a hought to ntea hysay h he caum-as hannes oatd n th saopasm tcuum mmane. Votag-dvn confomatona hanges n the votaggated cacum hanns thn

atvat th aum as om th saopasm tuum va potnpoten nteactons 13.The votagegated cacum channes n skeeta musce a Ltye (

They medate ongastng cuents h so votagdepndnt nactvatonthy hav a ag snghann ondutan aout 25 pS and a hgh votago atvaton and thy a spay nhtd y dhydopyidn aumhann antagonsts. Th nta uaton o Ltye aum hannsom seeta musce took advange o the hgh densty n ansvese tuuemmans to ovde an nchd stng mata and emoyed th secc

hghanty ndng of dhydopydne cacum chann antagonsts to dn-tfy th aum hann otn ( 8). htrogous suunt and (78 and assoatd suunts of 50 D and suunts o 33 (7) dented as omponnts of the acum channe n the nta uicatonstudes as assssed y g ug u g u




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OAGGAD ON HANNS 5

croegaden edmenaon. Subequen expemen demonaed ha hegnus suun and cnaind n nly pncpal 1 uun w

an appan mcul mass f 75 bu als a dsulfdnkd dm 2and 0 suun w appan mlcua masss 43 and 27 , scvy (673) s sul ge h analyss cmcal ppee o he ubun ed o a mde o ccum channel ubun ucuellusad n Fgu B 2 70) T spcc assan pens asa mulsuun cmp was suppd y cpucan ac suunh dydpydnndng acvy and calcumcnducanc acvy calcum cannl (67 70 74 75) y cmmunppan all spon by anbode deced agant he l ubun (69 0 76) and y

cmmunpcpan cacum can cmp ands agnseac aua subun 7779 Esmae chmey ndcaed ha acm cacum cann cmpl cnan appmaly ml eac e ubun The ocemcal and molecula ps ac e suunsf ea muce cacum channl a cnsded lw

e I ubun o keea muce cacum channe wa coned by layceenng baed on amno acd equence 8) The DNA pedc a pnf 873 amn acds w a mlcula g f 22 cnsdaly lagan emae 75 D o he uun o pued calcum channel

Ana o e bun pued acum channel and cacum channelsn ansvee ubue membane ung sequncedced ands seda m me an 9% we nced n e cayl emnal dmanbn sdus d sud n m a nsanomaou n D ge a 75 81 82) Ony a mal acon (le han1) cnaned he uengh 1 ubun encoded by he DNA B mae deeced n a eea muce ce n cuue uggeng ha boh may bepsn n vv 83) nce n mRA a ncds m aundan ncad m as n dnd ncaed m may pducd y pccpyc pcng n vv

e 2 suun keleal muce calcum cannels s a ydpc glycopon w an apen moecula ma 1 dgycylanand 05 a dglycylan 70 4) cnans b gmanns andcmp cabda cans Clnng and squncng cDAs a ncd 2 subun dnd a pn f 6 amn acds w a mlecua mass 25 mulple penal anmembane egmen and mulple conensue o Nned gcoaon 5 ue ) The pedced poen

as 20 age an h appaen mocul ma o h degycyad 2ubun whc uggd a a pn e pen ncdd y 2cDNA ma n b pen n maue 2 suun a ad n chaaczdbochemcaly uequn ud hae on a bh 2 and 0 ubunae encoded he ame mRNA ee beow)




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4 CAERA

The subunits re hrohiic roteins that are not gcosate an therefore are ike to be locate on the intracelur sie of the membrane (70)

The re hoshorlate b mutie rotein kinases incuing rotein kinase an cAMeenent rotein kinase which reguate the function of mancalcu chaels 70, 86-88) DA cloning an sequencg reveale arotein of524 amino acis wth a eicte moecuar mass of58 89) nageemen wth ochemca ata the rmary srucure oes not ncue anotentia transmembrane segments but contains mutie consensus sites forhoshoration b ifferent rotein knases Fig 2B)

The subuni f skeea use aum hannes s a hrhobi grtein wth an aarent moecuar mass of 30 without egcosation

an 0 folowng eglcoslaton 0). Clonng an sequencng cDAsencoing ' subunits reveae a roten of 2 mino aci resiues wih amolecular ass o kD 0, 1) e euce rimary strcture contanethee recte hrohobc transebrane segments an mutie sites for-nke glcosato

e 8 subut appears on SDS gels as a doube of and kD proteins,wc are oth rohobc an glcosate 70 9). Determination of theao ac sequeces o ets eve o th suunt showe that itwas ecoe the sae RA as te a subunit 9, 94). he mature a2suunit is tncate at alanne 94 of te a2 recursor roten resues95-1106 consttute the sue-lnke subunit This sequence encoes arotein of 16 an contains a singe transmembrane segment an threeconsensus sequences for inke gcosation he oubet on SDS gesreresents two ifferent glcosate forms of the subunit

b e he

e te seletal muscle calcu cannels te rcal carac calcu ca

es ae Le 95 6) Anboies aains a2 subunis of skee uscecalcium channels etect corresoning subunits in cariac rearations 9798) artial ure carac caciu channes aear to contain aI a2, an subunits 910) but te eatve ow aunance of calcu channes incaac tssue a te dcut of cotrlg oteoss urg legt uricaton roceures have frstrate attemts at comete urication of antact carac caciu canel comle Te al subunt with an aarent masof 165 to 190 kD has been irectl ientiie b hotoafnit abeingwt otoeacte oes , 00, 0)

Sbns of Pred Neronal Calcm Channels

Multle tes of calcum chanels which ier in hsioogical an hrmacologca oetes ae eesse euons At least three tes of hghvoltae-acvaed cacum channes hae been dsnushed n addon o Lye

Annu.

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VOGGD ON HNNS 0

050) ype P-ype ad Q-ype chaels all have needae snglechannel coducances abou 15 p) and can edae calcu currens wh

varyng raes of volage-dependen acvaon, depedng on her subuncoposo see beow ad o ohe facos. Tey e es dsngushed byher pharacologcal poperes: N-ye re speccay bed by -conoox GA -ype ae os sesve o -agaoxn IVA, ad Q-ype re ossensve o -conooxn MVC Because e concenaon of cacu cannesn skeleal usce ransvese ubules s uc hghe han n neuona ebaneshe bochecal popees of hese chnes n neuons e no as well esblshed Iuoprecpaon w specc anbodes gans subus revealed a coplex of olyepdes wh szes coesondng o and

subuns of dhydopydne-sensve L-ye calcu channes n e ban 79109 10). ovel kD proe was also dened as a speccall assocaedcopone of e L-ype calcu chane coplex fo ban 79 e-conooxn-sensve Nype ccu channes pued fo a ban conna subu a 10 kD 2lke subun and subuns of 60 kDa o 70 kD asdefed by abodes agans he seea uscle fos of hese subuns115) Boh Lype ad Nype cacu cannels fro ban appe o acka subu bu poes of approxaey 00 kD e speccally assoaed whNype calu channels as wel as Lype calcu canes fro bran and aybe addoal bran-specfc subus or assocaed proens 79 11 114 15)

pe m e Sb m e

Fve addoa gees encodg e ubuns of calcu channels have beendefed b DA clong ad sequencg usg he skeleal uscle subu as a probe ad hese are hough o ecode he ajor ypes of hghoage-acaed calcu chaels deed by physologca and pharacoloal poees 0 The subus fal o wo goups based

o ao acd sequece slary The cass C and D genes ecode L-ypecalcu chaes whch e sequeces ae geae han 75% deca oskeleal uscle -ype subuns he class C gene s he pay calcuchael he hear ad s wdely expressed n oher ssues The class D gees expressed n neuoedocrne cells ad neuons Te cass A, B and E genesencode noLype calcu channes, expessed pray n neuons, n whchhe ano acd sequences ae ony 25 o 0% dencal o he skeeal uscle subus I geeral he level of amno acd sequence deny aong he subus s greaes n he ransebrane regons and leas n he age

racellular loops coecg doas ad I and n he raceluaraoerma ad carboxy ernal doans. Mos of he subu genesaso encode aleavely splced segens ha ncease e olecua desy The fucoal sgfcace oaleave splcg has o ye been defedfor ay of hese sofors.

Annu.

Rev.Biochem.1995.64:493531


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50 CAERA

Fou genes enoding alium hanne subunits (14) have been haeze, n ee of s ve pe sp pus h ve en

identied (89,118-12 3). In general, the aino ai sequenes of he subunishave wo onseved segments in a ena oe egion n ae ivegen in theaboxy n anoeina sgmens A of he sofos hve onsensussequenes fo physphoyaion by mutipe potein inases Simiar isofonsof he subuni hv been esibe n un ssues (24)

20 RNAs e eognize by ybzon hgh singny whDNA pobes enoding the skeeta muse isofo ae detete in toa NAfom wie ange of ssues (85 125) Tese 20 pi nsip eppaeny the produts of the same gene bu e iffeny poesse in

humn issues o yied at eas hee isofos whih wee esigne byWs (24 s 2 (expess n see use 2 (expesse nneuonal ssues), an 2c (expesse in oa) (24, 12)

n ontast o he 2 an subunits, thee is no eviene toate fouip sofos of th subunis. DA pobes eve fo he ongsun of he y subun hybze o singe RNA spies fo semusle, but show weak o no spei hybrdiation in brain and severa othessues 9 91 126). Thus, the subunit may be enoe by a singe gene

whih is epessed pmail o exlusively in skeletal muse.Fucoa Roe of acum hae SubuLike the subunits o Na hannels he subunits of some alium hnnelsan serve as votage-gated on hannels when epessed alone These inludethe Ltype aium hannels fom heat (!) (127) and skeeta muse (128)and the lass A and subunits om at bain (293. Howeve, heauxliay subunits of aium hannels have substanti effes on expessionnd gtng of te 1 subuns

The subun of the skeleta muse Lype aliu hanne one esthe snthesis of a low density of funtiona aium hannes in ony a safation of the tansfeted els in a mammaian L el ine (128). The uentsexpessed n L es v es s sowe hn iu unsin skeea musle owev ouss of von n nvonof aium uens in these es wee iy ee by oexpession of the subunit 132 133) Coexpession of 2B an subunis halittle o no effet on the amplitue and knetis of aliu uents of theskleal muscle subuns expressed in L cels (132). However, 2 subunits

inas he aivy of pu um hannels onstue in ipi biys(134).

Epesson of the smoohmuse spe vaan of he ass subunin CHO cells also reveale substantial eects oauxiliary subunits Peacalcium channel currents were increase, the kinetics of activation and inac-

Annu.

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OAEAED ON CHANNES 5

ivaion were acceerae an he voage epenence of acvaion an inacvaon wr hf gh o mor ngav mmbran pona. Th (2

ubun ha furhr ffc on knc of acvaon.Expreon of mRA ha ncoe h ca C carac Lp cacum

chann ( ubun X n ooc aon ucn o rcecn nhe of a funcona cacum channe ha moua broprn Smar ha nco h avpce moo muc an bran oform of h ca C ( ubun rc hnh of funcona chann n h m 1313. T (2 ubunubana incra h ampu oh cacum cun wn co-prwh he carac ( ubun n ooce, acceerae acvaon annacvaon an h h voag pnnc o nacvaon o more ngv pol (127, ) Coxpo o h cadac uunwh he ubun nooce ncra h pak currn accraacvaon an hfe he voag pnnc of acvaon o mor ngavmmbran pona 3 10. mar ncra n pak currn wr obrv whn h ubun wa expr wh h vacuar mooh muceoo o h cadac ( ubun nooc 37 or whn h carac( ubuni wa xpree wih cariac ubun 121 141). Ahough he

P b dd no al h c o h ooh cl oo o hcarac ( ubun 7 h carac ubun accra acvaon of hcacum curren n ooc xpreng he carac ( ubun an he hevoag pnnc oacvaon o mr ngav mmbran pona 121,141 P wa mor c a ncrang currn han hr P or P' Thu,h pron nco b h frn ubun gn pa var c onh cacum currn ma b carac ( bun.

o-expreon of boh ( an ubun wh he carac ( ubun nooce reu n a geaer ncrae curren ampue, acvaon a more

ngav mmbran pona a pr voag pennc of acvaon aninacvaion an a mor rapi currn im cour comar o xprion ofhe ( ubun wh her of h ubun aon 139 1 Th obrvaon ugg a nrgc neracon beween acon of e ( an ubun on he funcona propre of h ( ubun.

Th apld o h calcu curn of h ( ubun of ca A, caB -p ca D L-p an ca E bran cacum chann are grancra b co-xpron of (2 an ubun 124 12, 130, 14214.Th c of ubun ar omnan wh promnn c o (2n mo expermn ubun o no hav a maor effec. n man ca,gncan xpron of cacum chann funcion on obv wenauxa ubun ar coxpr. Howver, nucear njecon of expronvcor in ooc gv hacd xpo o ubuniao29, 3 Unr h condon h ffc of auxar ubun on h

Annu.

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50

unctn l suunts ae seve mst claly, snce sustantal expessn the suunt alne s acheve cmpasn Wth the class B type

calcum channel the b suunt ncease expessn calcum cuentncease the ates actvatn an nactvatn an she the vltaeepenence nactvatn twa me neatve memane ptentals 29)n atn cexpessn > 2' 3 suunts wth a class A calcumchannel suunt causes a pessve ncease n the ate nactvatnwhch gge hat aemb of buni wih ifferen pbni rinsynthess calcum channels exchane psuunts n peexstncalcum channels may alte the unctnal ppetes 3 Lke the Ltypecalcum channels n whch the suunts ae unctnally autnmus utae moae y hei aoiae auxiia ubuni, he bni of neuonal nnLtype calcum channels can unctn as vltaeate calcum channels u they appea t eque the pesence asscate suunts ecentunctnal expessn, an expessn eent auxlay suunts altes thefuniona popeie.

Mha f Rglan by Sb

he mpance an muipii of he effe of he P ubni on aium

channel unctn ae stkn. In eneal th the nume hh-anty stesfo rg an oxin bining an he ampiue of peak aim en aeneae, he ime oue of he aium uen i bania aeeae, anthe vltae epenence actvatn an nactvatn s altee. hat mleculamechansms can accunt these multple eects? Expements t ate pvesme ntal clues o pssibe mehanim unelyn these actns. s nteave the suunt s a sustate phsphylatn y numeus ptenkinae an he the suunts have multple cnsensus stes phsphylatn Meve the P suunt s selectvely ephsphylate y phsphp

ten phsphatases ( 16 Thus, oexpeion of diffeent P suunts may nuceeent eulatn y pten phsphylatn/ephsphylatn mechansms. Snce ephsphylatn can nluence th the nume actve calcumhanne an he ae an exen of inaivaion of aim hanne (7 8the eects psuunts n these aspects calcum channel expessn anunctn may e ue n pat t phsphylatn/ephsphylatn mechansms.Alteatvely, ecent expements shw that p suunts als nuence theoping of gaing hage moemen o hanne opening (19 Le thevltaeate n channels, eplazatn vtae-ate calcum channels

causes a sees vltaeven tansmemane vements chae amnac esues n the l suunts that seve as atn chaes. Fllwn thsmvement atn chaes, the calcum channels can pen ut the palty openng s much less than .0. he a C suunts expesse inXenopus ooe oexpeon of neae e efen of oupng of



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OAEAD ION CHANNES 09

gatng chage movement to channe oening by -fod. This ovocative resutsggests hat the sbnt can lower the energ barier for oenng the channelore an can thereb ncrease k cacium currents wihout increasing he

numbr of cacim channes eresse Since the bining of ihoidinergs to these Ltye cacm channes is also inuence by channe stat it isconceivable that the number of highanity binding stes obseed in eressechannes s aso change b ths echansm whot a change n e actanmber of cacm channe 1 subnt roteins eressed. This mechanism oaction of the sbunits of the cacm channes woul be simar to eechans of action oosed for the sodiu channe 1 subunits at reducethe energy baer for shift of channel state to a fast gaing ode for sodiu

channes exresse n enopus ooctesA ste of interacton of P sbnts with 1 sbnits has been entife bya noe rarscreenng etho (0) cDNAs that encoe segments of thentracea oo between oans I an II of the 1 sbnit wee fon toeress fuson rotens that bn p subnits secical Coeression of thecorresoning etes reents the efects of subunits on eression andfncton of 1 sbnits Ths segmet of the 1 sbnt interacts with aconsere otif n the sbnt (11. This nteraction doman may mediatethe change n energy of actaton that inceases the efcency of cacim

crrent eresson on coeresson of sbnts

S UM HS WHNTRAELLULAR EFFETOR ROTEN

lcium-ls hnnls

In skeeta sce the te otagegate cacm channes n the transersetbe membrane ae thought to hysicay contact the yanoinesensitive

cacreease channes n the sarcoasc retcm (R membrne Votageven confomatona changes n the votagegated cacium channesseve to actvate the cacumreease channe through roteinotein interactons Ths the cacmreease channe seres as an effector of theoltagegate cac channe n the ocess of ecitatoncontracton cong Mce th the muscular dysgenesis mtaton hae efecte ectatoncontraction coing e to a mtation n the subunit of the skeleta mscecacm channe (12 njecton of an eresson vector encoing the 1sbnt restores ectatoncontracton cong. he ste of nteracton withthe cacmreease channe s n arge ntracear ooconnectng omans II an of the 1 sbnt 13 Eenty ths loo can transmt asgna from otageeenent actvation of the transverse tbe cacimchannes that can actate the cacmreease channe




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5 CAERA

p b Neuonal calcium channels in pesynaptc neve temnals ntate the pocesof neuotansmtte eease by alowing the apid enty of calcium in esponseto depoaiation he inceae in calcium concentration which initiate neu-otrntte elee i hihly oclied nd peynptic clcium chnnel ndynaptic vesicle ae thouht to be coely oited in actie one. ecentevience inicates that this association may be meiate n pa though bnin of pesynaptic calcium channels to ynaptic membane potein Ntypecalium channels, which ae involve n eease of neuotansmittes at manyynpe, bind to the ynaptic plama protein yntin nd poiby lo to thesynaptic vesicle potein synaptotamin 154-156). ecent tudie with fusion

poteins epeentin diffeent sements of the Ntype calcium channe lsubunit show that the site o inteaction is in the intacellua oop betweenhooogou domin nd 157) hu, the intcelulr loop betweendomain and may seve as an effecto inteaction domain fo neuotan-mtte elease in pesynaptic teminals as wel as fo excitationcontactioncoupling in seletal muscle. itional inteactions o this omain o calciumchannel l subunits may paticipate i othe celula signaling pocesses thatae initiated by depolaization o by calcium inux

RR O O K NNBN

p K+ Cheoltet K+ chnnel e functionly divee 158-160). hey cn becasiied ito two majo oups based on physiological popetie: delayedectifies which activate ae a elay following membane depoaizaton andeithe inactivate slowly o o not inativate at al, an type K+ channelswhich ae fatactivatin an inactivate. he molecula tuctue of the volt

agegate + channels was st eveale by molecula coning of the gneencoin the Shakemutation in Doha 160, 161) Atype K channelan elaye ectie + channels in osoia an vetebates have pncipalsubunits whose polypeptie bacbones ae 60 to 0 D and ae homologousin tuctue to a ingle domain of the o ubunit of a + o a+ channel(Fiue 2C hey fom homotetames and heteotetame that ae fulyfunctional a voltageated ion channels, and they ae alteativey splicedain aditional diveit (160 161 Howeve, seveal lines of evidence nowindicate that, lie Na+ an Ca+ channels, they contain one o moe auxiliay

subunits as components of thei oliomeic stuctue n itu. Cmp ed Ne CheSome bain + channels contain a ecepto fo enotoxins (DX, a famiyof neuotoxins iolated from the venom of the blac mamba snae,

Annu.

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OAGGA ON ANN

Dendi lei 16) These bsic oypeptide oxins inhibi AtypeK+ chnnes resuing in he fciitin of neuronsme eese nd eietifm civity The DTX bining site is he ece fo hree ditionpeptie ignds: ms ce egrnuing peptide MCD jbungotoxin jBTX nd chybdooxin TX) 162 hese toxins hve been successfuyused s mecu prbes identify nd pufy comnens of Aye ndeyed ecie chnnes om min bn

Photinity being o otssium chnnes wih bungotoxin evesie cmnens f rimey 7 kD n 8 kD in chick brn 16Pucion o DXbining poeins m deegentsubiized mnbin membnes evee noncoveny ssocied gycopoein compex

cnining oyeides f 7480 kD in ssociion wih sme poypepidesf 42 , 38 D nd 3 when nye by SDSAGE 164166 he D oypeptide ws obseved in vibe mouns nd my be poteoyticmen f ne e ther yeties 164 inding f e25I)DTX ndr t2 ] MD the pued eceptr ws nhibied by BTX demonstingtht + chnnes wth binding sites o thee gnds wee copued he8 kD Dbining rein frm r brin reresens fmy phmcoogicy nd stuctuy eted gycpoteins 164 167 168 Neuminidseetment reuce its pen moecu weght t 70 nd subsequen

remen wih endgycsise F futher reduced this o 6 kD inicing ththe 80 D subuni s siyed membne gycopotein tht is exposed o theeceu sufce n conts tretment the 38 poyeide wihneumnse enycsse F n effec n is mbiiy n DP inicting h ths cmpen st e d no conin Nnedugrs 68 6) The temin mn ci sequence o the 80 subunfm bvine brin ws viuy ientic o th deuce fm he cDNA ofhe muse/r hmgue he Shake my + chnnes RK MK2/RB2 chnne ren r bin known o be DTXsensitive

eye recifier 66 168) This cncusivey emonstrted h he DTXeceto ptein s K chnne

Antibes ginst uson prten geneted rm DNA th encodes deyed rectie K r chnne poypeide rm t brin 170) wee used idenify its rtein cmnens imir to K chnnes ientifie vi heirsensiviy DTX hs putve eye ece chnne so contined ow moecu weight subunit ntid ntibdies specicy iunecited cme f 30 kD n 38 yeides Becuse he nibies

recgnied the 30 D ypepie ecusivey nd copecipited the 38

subun s cncue h hese oypetides were immungicyisnc ens n heerigmec me h : sichiey Tusbh deye recier n ype neuron K chnnes my hve subunitsigue .

Annu.

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5 CARA

e pee x r eRcn work b Sco a 171) ha rsld in conin and rimar

srcur drnaion o h rs assium channl auiliary subuni Th bni o h dndooxin-niiv oasim chann rom bovin brainis a proin o 37 amino acids which has no hydrophobic smnsand is no coslad s ano acid sunc conains svral consnsussis or roin hohorlaion and h roin is raid hoshoadb cAMPdndn in kinas Anasis o babl sconday scrrvals our maor pobabl alha hlical sns. In all o hs rspcsh poaium channl subuni cloy rsmbs h cacim channl buni Howv no xndd amino acid sqnc homoo is dcabl

indcan a vouonay aionshp wn wo proins isdian

i h cacium chann ubuni oaim channl buni havimpoan uncional c whn coxprsd wih subuns T mcour o bo acivaion and inacivaion ar acclrad 172) Morovrmui oaim chann uni hav n idnid and hy havdirnial cs on uncion o h subnis Thus h poassim channl bni hav a unciona analo wih cacim chann bnis aswll a a nral rcural imiariy I wil b o inrs o drmn

whhr h mchanisms o acion o hs wo class o auxiliary subunisar imilar

SA BASS N HANNE NN

urcaion molcuar conin and drmnaion o h primary rucurso h prncipa ubni o sodium calcium, and oaim channl havpo a oca pa o pon aonp wn h

srcr and ncion [rviwd in 2 173 174 Th scr o h rincialsubunis o ach o h channl i bad on h sam moi Fir ; siur ao ou homooou ansmmbran domain which conain ixprobab ransmmbran apha hlic and surround a cnra ion por Inpoasium channls ach omain i a spara n produc and h ncionachannl i a homo- or hro-ramr In sodim and cacim channl ordomain ar conaind wihin a sin nciona or sbni. Alhohach chann conain aociad axilia sbni h incial bni cancarry o h baic uncions o h vola-ad ion channl b hmlvand hror mus conain h ncsary cura lmns or ion channlncion wihin hm Thi scion rviw h crrn saus o rsarch onh mocular basi o h hr major mn o vola-ad ion channncion: voadpndn acivaion ion condcanc and inacivaion.




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OAEAED ION CHANNE

VOGE-EPEE VO

Ativation of th voltaggatd ion hannl i thoght to lt from a voltagdivn onformational hang whih opn a tranmmban po throghth potin. Dpolarzation of th mban rt an tria fo onvoag no ha onan h gang hag of h hann oad whnth tanmmban trial ld h gaing harg r liky to bhargd amino aid sid loatd in ranmmban o mmbanaoiatd gmnt of th protin h mvmnt of h gting hrg f hdim hannl hogh th mmban dvn by dpoariatin ha bndity asd as an otd gating nt 1) h gting nt fo

odim hannls wa statd to orpond to th movnt of pproimaly ix hag all h way aos h mban; movmn of a largnb of hags aoss a fation of th ban ltri ld wod bqivalnt. o dtaild analy of potaim hann gaing rrnt ggst vn lg gtng hg ovnts dntiation of th voltagsnoand gating hags of th voltggatd ion hannl i th t ritia tptoad ndtanding th olla bai of voltagdpndnt ativation

nston and anayss o th ay strt of h odi hannl sbn th s b of h volaggad ion hannl gn famly ld o h

diton tht th foth tnsban sgnt n ah doain (th S4gnt ght sv th voltag snso2 3 16 h gnt ontainpatd otifs of a positivy hargd id folowd by two hydophobsids Fo opaison aong dfnt hannls ths poitiv hag havbn nbd sntally fom th allla nd of th gmnt (Fig 3).h dton tht ths ost v hags sv as gatng hag has bn ttdy gnss and ssion sds of oh sod and potas hannln h a th gating hag has bn infrd fom mamnt of thtpn of voltagdndn ofhannl ativation at ow lvs of ativatonwh this povids an indit timat of gating harg

Ntalizton o th fo ostvly hagd id in th S4 gnt ofdomain of th odim hannl by itditd mtagn ha ajo tson th voltag dpndn of ativation 77). Ntlization of th agininsd in osion (R hd ft on h n of od hannativtion, bt ntalization of th positivly hargd id in poition 2thogh 4 n h S4 gnt dd th appnt gating harg by 09 to 1.hags. Combind ntalzation of ltipl hagd id and taton

o ostv hgs to ngtv hags a pogvy inasing dtion o gatng hg bt th dion o ant gatng hg is lss tanpopotion to th ptd dton n total hg of th S4 gnt nddon os of h ons so d h of h volg dndnof tivation to o positiv o o ngativ mban potntials.

Annu.

Rev.Biochem.1995.64:493531


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CAA

Figure An S4 sgmnt of K chnn Th S4 sgmnt of t Shkr K+ chnnl ofDl iuad a ba-ad-i apa a e id td in d piivy ad mio aid i vy d piio a nmbd fm th x ndo i

Netraiation of the ositively charged resides in the S4 segments ofpotassim channels also cased redction in apparent gating charge and hisof the voltage deendence of activation 178180). For the k otassimchannel of D netraliation of R (Figre B) cases an nepect-edly large redction in aparent gating charge whie charge reversa has littleadditional effect 179 180. ost mtations at this site cased a ositive shiftin the voltage dependence of gating (179 180) n contrast netraiation andcharge reversal at R2 and K7 cased changes in aarent gating charge thatwere closely correlated with the changes in charge cased by the mtations

179 180) and netraliation of R3 cases a sbstantial redction in onecomonent of gating crrent 181 . Analysis of the shifts in votage deendencecased by mtation of each of the positivey charged resides in an S4 heihoed an alteating atte of voltage hift for mot reide ositive hiffor netraiation in ositions 3 and 7; and negative shifts for ositions

Annu.

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OTAEAD ION CHANNE

and 4 8 Only he arginine in posiion 6 deviaes from hs pae heseresus are consisen wih a mode i whch of the gatng chges nodd-numbered posiions make sa brdges tha sbize he acivaed ste

whie ose in posiions 2 and 4 make sa bridges ha sabze e cosedse 180 18) Ms ms h rede stve hge R sed negave shf n he voge depedene of avt e se a K seda psiive shf vera, he sdes of S segmet ss hae gtgsuppo he concusion ha he posive charged residues in hese segmensare indeed gang charges invoved in he voage sensors of he ion channes

he ndvda resdes pper be dffere he ver appare gag chge, ad her se d he es (ter t chrge)

aso have ipoan inuences on gaingIf he 4 segens us move hough he poen srucure durng hepocess o acvaon he sze and shape o he hrophoc resdues n hesesegens shoud aso have an imporan infuence on vogedepende acvaon Muion of sge euine resdue o pheaanine S segmeno a sodiu hanne shis he voage dependence o gaing 0 mV 183imary maion of severa hydrophobic residues in the S segmens ofpoassium channes aso causes dramaic shifs up o 80 mY in he voagedependence of acivaion 84, 85 In conras, muaions of severa hdro

phb resdues her ransmembrne segmens dd no have major effeo acivaion 85) hese resus, ogeher wh he effecs of charge euraaon uaons provde srong supporfor decaon of he S segmensas he voage sensors of he voage-gaed ion chnnes and for idencatono he posiivey chaged esides wihin em as he gaing charges of hehnne

The mechanism whch he 4 segmens serve as voage sensors s oknown he "sding hex or "heca screw modes 2 16) poposed hahe enre 4 hex oves across he membrane aong a spira pah exchanging

ion pair panes beween is posiivey chaged residues and fxed negaveharges n suondng ransembrae segmes s mde mes rgebu unknwn energy barrier for breakng and remakng numerous on parswhin he poein sce, and sggess an appoximae equivaence of gaingcharge oveen among he differen charged residues in he S4 heicesBecase neaaon o ndvdua chaged resdues has very deen eecson he voage dependence of channe acvaion is unie ha s simpeode can e coec in deai A more ompex "propagang heix mdepoposes ha he 4 ansmemrane egmens undergo an apha heix-beashee ransion which propagaes oward o move charged residues acosshe eane (176. his ode aso has no direc experimena suppor, bui has he poenia o accoodae a eas some of he dfferences observedag ndvdua resdues becase no chrge resdues e S segme

Annu.

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16 CARA

re propo ed to move the me di t e ro the membr e hu thoughthe S ege t re e r y ip ited he otge eor o he otgeg ted io h e the meh i m through whih the ii ti te ti tio o

the h e remi uko .

A

E e ti y mode or the tru ture o the oge-g ted io he i ude tr membr e pore i the e ter o u re o homoogoutr membre domi E h doi i hee ode wou d oi ute oeourh o the w o the pore. Ideti tio o he egmet whih ie thetr membr e pore d de e the odu te d io ee tivit o theh e i o gret itere t d importe umer o toxi drug diorg i tio re b o ker o the votge-g ted io he I ever e de ti ed biophi y i o their eh i o tio idite th tthe e moe u e e ter d bid wi thi the tr membre pore o the he d ome te i th erme t io or ou o the ore 186 The ehe b o ker thereore erve moeu r m rker d pei pro e o the pore regio o the io h e mio id re idue h t orm the ex e ur d itr e u r mou th o the tr membre pore h e ee ide

tied by their i ter tio wi th porebok g dug d toxi The Exe h he e

Te trodo toxi d xi toxi re though t to b o k odium h e by bidigi th high i ty to the extr e u r mou th o the pore 186 Their bidigi o pe i th t they ere u ed m rker i the iiti puritio o odium h e rom ex i tb e e membr e ok o their bidig bypro totio or ovet moditio o rbox re idue ed to the mode thtthe e tioi toxi bid to rig o rbox re idue t the ex tr e u r

mouth o the oe 86. The e e idue h ve o bee ideti ied by i te-direted mutgee i . Nod e t 187 eutr ized gu 3 87 i r t br i odiumhe I I by mutgee i to g u tmie d expre ed d ed the u tio proper tie o the mu tt he. The ii t or te trodo toxi redued over OOOO- o d. Thi mio id re idue i oted i egme t S S igure d o the ex tr e u r ide o the 6 tr membre egmeti dom i I o the odium h e . Sub e ue t ex te io o heir y i ide ti ed idi mio id re idue i the e po i tio gu 3 87 i e hdom i th t ere reuired or hi h- ity tetrodo toxi bidig 188The e re idue re there ore ike y to urroud the extr e u r opeig o thepore d o tribu te to re ep tor i te or te trodo toxi. I ddi tio to the rigo rbox re idue e od rig o mio id oted three re idue othe mio termi ide o the e i o reuired or te trodo toxi bidig




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OTAEAD ION CHANNE

igue Prefrmig gi f e mgs dmais f vagega i caes e

rasmembrae fdig pae f a sige mgs dmai f a vagegaed i cae issaed as i ge e s segmes SS ad SS ad e f am aid esidesad egmes w ave bee mpaed i fai isaed Oen le esidesreuired fr i duae ad seeii f K+caes oen que esides eid f icdcace ad eecivi f a+ ad Ca+ cae ded le esides eied f igaffiy bidig f pe bke f K cae; lled le eside ied f cdcace ad dig f p blkes f + caes ded b sme f caesbidig peyakyamie pe bke

(Fiues I nd 4. These e cidic mino cids in domins I nd II bsicin domin nd neutl in domin V f this reion is i lph heicconformtion, this secon set of residues requied for tetrootoxi bindiwould fl on the sme sde of the hel nd form second inner rin of resduest the openin of the poe

Cdic sodium chnnels nd tetrodotoxin wth 200fod ower ffinty hbrin o skeetl muscle sodium chnnels but rein l of he eih resiuesdescibed ove tht e equired fo hihfnity bindin oweve, t position 385, two esidues towd the inotermin from lu387 in he binsodium chnne sequence, thee is chne of tyosine or phenylninein the bin nd selet uscle chnnels to cysteine in the cdic sodiumchnnel. uttion of this esidue fom cys to phe or tyr cuses n increse of200fold n the ffnt of the d odium hnnel nd the onvese muttion cuses loss of ffinity of 200fold in the bin o skelet musce chnnel99 . tht esdue so ontiutes in n essentwy to the tetodotoxin ecepto site Cdmium is hihity blocke ofcrdc sodum chnnels ut not o n o skeletl muscle sodum chnnels.

Substitution of this cticl cysteine in the skeletl musce o rin sodiumhnnel ones hhnty blok y dmum on these hnnes 89, 90)nlysis of the volte dependence of cdmium lock suests tht this ionpsses 20% of the wy throuh the membrne electric eld in rechin itsbindin site fomed y his cysteine esidue 90). Thus this residue my be

Annu.

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8 CAERA

approxmatey 20% of te way troug e eecrca fe wn e pore ofe soum canne

Te outer ou of te potassum anne as been mappe n a sma

wy The poypepde cybdooxn s n exceu boce o possumcannes wc ns n te outer mout of e pore entcaton of amnoacds wc contut o bndng o caybdotoxn reeas gutamc acasac ac an eonne resues wc ae reure for gafnty bnng 9 93 he equed esdues cuse on boh sdes o e SSSSegon s used n Fgue 4 nd e esdues coses to hese so segmensare most mportant or carydotoxn bndng onerson o any of teseresues to a postey carge amno ac ncreases e K for carybotoxn

ndng more tan 00-fod suggestng at postey caged amno acds nte toxn may normay nteract w e negatey carged an yroxycesdues n ese posons n e wdype cnne

Teraehyammonum ons aso bok poassum cannes from te extraceuar se. Anayss of ter afnty forb of te same famy of poassumcnne mun ee esdue on bo sdes o SS nd SS eequed w e mno cd esdue n poson 49 on e cboxy emnsde o SS beng domnn 94 Tyosne o penynne n s posonconers g-anty ock Caroxy resdues n ts poston ge ntemedate

ny nd posvey cged esdues peven eeymmonum bndngcompeey 94 enyaanne resdues n s poston n a four subuntso possum cnne cn pcpe n bndng eeymmonum onwc suggess e ou peny ngs coodne snge eehymmonum moecue oug con ob necons 6 These esduesare smar n poston n te amno acd seuence to tose tat are reureo eodooxn bndng o sodum cnnes hus seems ey e

etyammonum ons n potassum cannes an terootoxn n soum cannes occupy smar receptor regons at te extraceuar mout of te porewen tey bock te cannes.

h e h he

Loa anestetcs and reated antarytmc dugs e ougt to nd to aeceposte on e sodum canne tat s accessbe ony from he ntraceuarsde of te emrane and s more accesse wen te sodum canne s open186) Smary te penyakyamne cass of cacum canne antagonstse cceed as nceu opencnne ockers nd eeymmo

num nd eed monoymeymmonum eates can ock potassum cnnes om e nceu sde of te embrane wen te canne open 86 o bocemc nd moecu boogc ppoces veen used to pobe e pepde segments of e pncpa subunts of tevogegd on cnnes nec w ese nceu poe oces.

Annu.

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VOLTAGE-GAD ION CHANNELS

Verapam and relaed phenyakyaine cacum channel anagons drugsare the highes afnity igands among he diverse inacelular pore blocers.Desmehoxyverapam and s phooreacve azido derivave ludopaml have

or equm ndng o pued cacum channels n he range o 30nM and herefore can be used as hghly specfc bndng prbes of herrecepor se n he nracear mouh of he calcum channel Covalen labling of puried calcium channels wih udopamil results in incoporaion inohe l subun ony 97). The se of cvalen labelng was locaed by eensve proeolyc cleavage of he aeled subun followed by dencaonof e phoolabeled fragmens by mnoprecpaon w se-drecd anpepde anbodes (197). All of he covalen label recovered was ncooraed

nto a peptide ragmen conainng the S6 segment o domain IV of the subuni and several ano acd resdues a he nracellar end o his ansmembrane segmen nce phenyakyamnes ac only rom e nsde o hece was conclded ha he nraceluar end of ransmembrane segmenIV56 and he adjacen nracear resdes form par of he recepor se forphenylayamnes and hereoe pa o he nracelular moh o he calcmchannel (197, 198)

nalyss o maons ha aler ock o poassum channes rom henraceuar sde by eraakyammonum ons pon o boh he amno acd

resdues bween 1 and 2 and he nracellular end of he 6 segmen ascoponens o he nraceluar moh o he pore uaon o a cricalhreonne resde (poson 44 n he Shake poassm channel) n he seqence eween and 52 o he cosey reaed amno acd seine sscen o ncrease he or ock o potassum channes by nraceluareraehyammonum on Ofod 99) Teraehyammonum mus raverseony 15% of he memrane eeccal ed n reachng hs bndng se fromhe nacea soon hs, s kely ha hs eonne esde fomspa o a ndng se or eraehyammonm ons a he nracellar moh

o he posum channe kyehyamonm ons wh ong carbonchans n he alky group aso reqre hs hreonne resde for hghanyndng and bock n addon muaons of a hreonne resdue near he mddleo he 6 segmen (poson 469 n he Shake channe) o a hydrophocresdue ncrease he any orC8 and O akylehyammonum ons (200) more hydrophobc resdue n ths poson gves hgher any or healkyrehyaonm ons and he eec s greaer for larger alkyl subsens conssen wh hydrophobc neracons beween resdes a hs poson

an he ay gop o e sse eraalkylammonum on Thus n poassm channes as we as calcm channes 97, 98), he 56 segmenscone o omaon o he nraceuar moh o he pore and o bndngo hyopho poeocng gs

Loca aneshecs whch bock Na+ channes aso nerac wh amno acd

Annu.

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CAERA

resides in S6 segments Analysis of the S6 segment in domain IV of he Na +channel sbni by alaninescanning magenesis revealed two aromaticamino acid resides in positions 1764 and 1771 which were reqired forhighnity binding of a lcl anesthetic (01 ) ese w resides are lcatedapproimael 1 A apar on he same face of proposed S heli andmay inerac with he aromaic and posiively charged amino grops of hedrg molecle which are spaced 10 to 1 A apar I is likely ha teseporeblocking dgs also interact with amino acid resides in the S6 segmenof other domains of he Na+ hannel as they bind wihin te pore srrondedby all for domains.

I v

Consisent with the idea tha he amino acid resides that are reqired forbinding of pore blocers are also reqired for ineracon wih permean onschanges in these resides hve drmtc effecs on ion condance and selec-iviy. A clear demonsration of the close relaionship beween he amino acidrsids tht dtin pr lcn prpies nd thse tht dtmine ncondctance and selectivity came from stdies of chimec ptassim channelsin which the SS 1SS2 region is ansfeed between chnnel types hat differin bth singlechnnel cndctnce and anity fr tetraethylammnim ion

at intracelllar and eracelllar sites (202) Sch chimeric channels have heion condctanc afnity for extracelllar tetraethylammonim ion, and anity fr intracelllar tetraethylammonim ion specied by he SS 1SS2 regionwih lile effect of he remainder of he channel srctre Small changes inindividal amino acids wihin this region also have dramatic effects on ionselecivity (Figre 4) Changes of hreonine o serine or phenylalanine to serneincrease he condctance of Rb+ and N (203) Coordinate changes of lecinet vline nd vline t islecine in tw potentilly interacting positions in thedeep pore region are responsible for he differences in condcance and bindinganiy for inracelllar eraehylammonim ion beween chimerc hannelswhich differ in the SSl/SS2 region (204) Deleion of two resides (yr44gly446) from the SS2 regin of the Shake volagegated potassim channel yild snc siilr in lngth t th cspnding rgin f th distantlyrelaed cyclic nleoidegaed on channels ases loss of poassim seleciv-iy and increased hannel block by divalen caions which are haracerisicof the cyclic ncleotidegated ion channels (20) These reslts indicate haeven small alteraions in the amino acid resides in he SS 1SS2 region have

ccial effects on ion condctance and selectivity sppoting the conclsionha hese resides fom pat of the lining f he transmembrane pore andinterat directl with permean ions Moreover changes in amino acid seence in this rin can aso dtmine ion selectivity popeties of differentfmilies of ptassim chnnels. t is srising that s many of the amino acid

Annu.

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VLAGEGAD IN H 21

reide i thi regio are hydrophobic ad that hydrophobic reide arecrica deermia of io eectiiy remai o be deermed how heereide iteract with ermeat io to aow raid ad eectie io codc-

tace.A for poaim chae, chage i he amio acid reide i the

2 regio that are importa for bidig of the pore bocer etrodotoiae ao crica deerma o odi chae io codcace ad eec-tiity. igechae codctace ae for mtatio which etraizeige charge amog he i egaiey charged amio acid reide thatare importa for tetrodooi bidig ao redce igechae codc-ace, i ome cae to a ite a 10 of widype ee 188) odim

ad caci chae hae iia oera trce bt trigy diffeeio eeciiy odim io are eeiay imemeat throgh cacimha i h e of aim b ae aidy rmea i the abeceof diae catio 186) Thi property i hoght to arie from highaitybidig of cacim io o wo ie i he io codcace pathay thatboc odi io ery ad ao rapid cacim codcace. Cacim ioae e ha 0% a ereabe a odim io hrogh he odim chae.eaaby aio of oy o aio acid reide i he odim chaei cie o cofer cacim chaeie permeabiity properie 206)

Mtaio of yie 122 ad aaie 1 o egatiey charged gtamatereide ot oy aered tetrodotoi bidig bt ao caed a dramaticchage i he io eeciiy of he odim chae from odimeecieto cacieectie addiio thee chage creaed a highaity ifor cacim bidig ad boc o mooae io codcace throgh heodim chae a ha bee preioy decribed for cacim chae Thi e mta odim chae wih two additioa egatie charge ear theexacea moh of he aie oe regio ooae caio codcace i high i he abece of caci A cacim coceratio i the 10

M rage mooaet caio codcace i trogy ihibied by highaiy caci bidig. A cacim cocetraio are icreaed, cacimcodcace i preferred oer odim codctace. Thee re mirror heio codcace ropertie of caci chae ad idicae ha a eytctra deemiat of the io eectiity differece betee cacim adodi chae i ecied by the egatiey charged aio acid reideat the moth of the ptaie poreforig regio

Thee o a+ chae iy that the coeodig amio acidreide i Ca chae ae ao imora deemia of heir ioctit oitt it ti pctto ttio o t copoaio acid eide i caci chae doe cae ared ateratio iio eeciiy io bidig ad boc of the pore by diaet catio (08 Thee re deorae he otace of amio acid reide i




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nlogou pon whn he poe egon in deng e l N+nd Ca2 hanne

INTV TIN

Fast Inctivon of Sodum ChnnelFt tt f h su hannl qu ot ofit ol dendene ouplng o lg-dendnt atan and h inia pr

n piialy prevend y remen he nracellular surac of hdum hnne wh prelyi enz ese ul ld o he prooal utnhbty "bndhn del fo iu hannel nacivn n wih an nvon pacle thed on he nacelu sua the odu hannel (the bal) due t a eept it n he intacellulmuth o h po bnd, and bk pe dung he pes o nacaon(175). Ths e pedcs th n nacat gat on h nrcelula suac sodium chae ay rpobl d ntvtn.

he sd hnne eents ht ae reuired f ination heen dnied by u of pane of tedrecd antpde nibe gint

peptde endn h 5 t 20 du egme e a uuni.These ntpide nibie wee pied t he nelu e o hesou channe m he eding pp in whece vge cp expent m e bhng sun i singlehannel recrding ement inx ndu mbn ph (09 10). In boh e on oned dd sh nellu een nng hlgO ns Fgur 5) nhbed sdum hnne incn nhn incin f nibyded dim hannen embn phs was oplee e b d ff f bywee volgdenden At negve ebne potels a whh odu inactvted, he nby bound apd and nhbd hnnelnto; o oe mm n a whh he du hnnel inived, iby bndng nd on wee geatl lwd o pe ventd Baed ese reuls i oed h he emen ha thanbody ogne dey nvoed i n he noona hang leangto hnne ncon Dung hi onfotn hn th nacongang segn wa poed o od no the hanl er thnan a b ludng the ranran p, and e nesl o nty bndng 209 1 gue

d upoed b dtd ugene peens

EXpeon f he du hannl uun n ye a wope ondng h he dn nd h ouh dn resusin hanne h ve nly u inve 0fd oe owy han

Annu.R

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OTAEAD ION CHANNE

Mechansm of inactvaon of Na+ d K+ channls. hng-l mchansm o Na+cnnl ncvon (A) nd bllndcn mcnsm of + cnnl incivon (B llurad Th nrcllur loop connctng omns III n IV o h N+ chnnl pc

foming ingd lid T cicl idu lu7 L nd 14 () on oluding ncllul moh of h po n h K cnn nd N cnnl scly

nom. e yiooc cceic of ee c cnne e im ooe of odim cnne i incivon blocked by e iedieced ni-boy. n con om cnne bn c beeen omin n ve nom fnconl oete ee wo ndeenden oce ingedeced nboe nd c mion ovide on or fo ienifi

con of e o nrcellr emen connecin domn III nd IV nincivion in loo.e incivion in oo conn iy conerve ce o oiivey

ce nd ydoobc mno cd ede. Neliion of e oiiveyced mno cd ede in e incvion in loo of e odim

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4 CARALL

he by sitedieted mgeesis ds ot hve pofod effect ohe itivtio 1 1 1) lthogh etlizio of e ste of pos-ie haged esides t the motemi ed of the loop does sow

itivtio and hit the oltag dndnc o boh tivtio d itivtio 1 I otst deetio o he mio id segmet t he miotem ed of the oop ompete boks fst soim he itivtio1) Ss of the hydophobi amio id esides i tis segmet of theitivtio gtig loop by mttio to the hydophii bt hged esidegltmie show tht mttio of he theeeside ste IFM to gtamieompletely bloks fst sodim hel itivtio 13) The sigle pheyllie i the ete of this lste t positio 148 i sodim he II isthe itil rside Fige 5) Covesio o this eside to glamie issiiet by itsef to lmost ompletey pevet fst he itivtioMttio of the djet isoleie d methioie esides to gtmie lsohs substantial fcts. Substitution of gltme fo ioucin slows inacti-vtio fold d makes itivtio iomplete evig 10 sstied -et t the ed of log depoliztios Sbstittio of gltmie fo methioieslows itivtio 3fold he itetio of phe148 with the eepto of theitivtio gtig ptile is liely to be hydophobi bese thee is oseoeltio betwee the hydophobiit of the eside t tht positio d the

extet of fst sodim hel itivtio 14) O the bsis of these esltsit hs bee poposed tht these esides serve s the itivtio gtig pieeteig the itell moh of the tsmembe poe of the sodimhel d bokig it dig hel itivtio The itell oopbetwee domis III d I theefoe seves s itivtio gte d oseshe tsmembe poe of the sodim hel fom the telll side ofthe membe

is mode fo itivtio implies t the itella mo of the poehas cto site tht ids th nactaton prtile I geemet with this

petpeptide otiig the IFM motif estoes itivtio to mat Nhels with phe148 epled by gltmie 15) he feey diffsibepeptide estoe itivtio with the pid kietis d steep voltgedepedee of the tive N+ hel Altetio of the IFM motif by sbstituton of gutamn o lie esides pevets estotio of itivtioconsitnt with th concluion that th ntatid do indd bind to cto that us the sme stuctu s the itivtio patile itself

A didte fo the itivtio gte eepto egio hs bee idetied byliesig mtgeesis of the S6 segmet i domi I 16) Matio

of thee det hydophobi esides t the itelll ed of this tsmmban sgmnt to alanin oducs Na channl that inactiat incom-ltly hvig gete th 8% of thei N et emiig t the ed of15 ms depoliig plses his mttio lso ses pooged siglehel




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VOTAGEGAlD ION CHANNES 55

pnings and frqunt ropnings that ar chaactisic of Na channls inhich th fast inactiation procss has bn disruptd This sit is on hlical

t n th intacllla sid th ain acid rsidus that a rqird frinding ca ansttic dgs is a pvid a lcla lananf th nding that cal anshtic drgs can trappd in th cannl byclsur of th inactiaton gat 86)

A Hed-d Mode o odu he F Ivo

h ppsd inactivaion ga is a sho stucturd lp of th channl hichplacs th inacivation paicl (M clos to h ou of th ans-

ban por Th inactiation gat loop rsmbls th hingd lids of allostic ns tat a gid ppid ops that fld n acti sitsand cntrol substrat accss nfrmatinal changs inducd by th bindingf allstrc ligands mv th hingd lid aay frm th activ sit and allsbstrat accss and cataltic aciit n analog to th allostric nsit has bn proposd that th sdim channl inactivatin gat functions asa hingd lid that ivs t plac th inactivatin particl in a psitin to bindt t intracllar mth f h transmmbran por of th sodiu channl

(2 (Figur T thrdimnsinal strcturs f sm hingd lids fallstrc nms that a nn rm ray crystallgraphic and todi-mnsinal NMR stdis prvid a aluabl srctural mdl fr dsign ffuhr pts to dfn th chanis of sodiu channl inactatonin dail.

vo o ou he

n cntrast to th rslts obtaind ih sdiu channls th inactiation

aticl snsib apid inactivatin f potassium channls b cclusin t ntaca t t p s cad at amintrinus ptid (217) . Ra f th amintrminus b dltion tagnsisprnts fast inactivation. Mtatins o singl psitily chargd aino acidsin that rgin slo inactiatin and mutation f lu7 to a hydphilic aminacid rvnts fast inactivatin alst cplly (7. r pptids ithain acd sncs dld n t inactivain paicl s fas, vl-agdpndn inactivain t mtant passium channls hos aminotniha bn dld 28. Ths sults t pctations of th balland

chain odl f ion channl inactiation oiginall proposd for sodiu chan-nls b Astng and Bzanilla (rvid in 7 h amintinalsgn f th otassi cannls is nvisind as an inacivation aticlthrd n th nd a chain f apprimatl an acids Figur Th positily chargd and hydrophbic rsids in th ball ar thught t




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LL

nteact wth an nactvaton ecepto a the ntaceula mouth o the channelthough a pocess o estted duson and bndng hs mehanst mode

pedcts that shotenng the han o amo ads onetg te a to eest o the channe shoud acceleate nactvaton whe eongatng the chanshoud sow natvaton he mode aso pedcts that extaceua pemeantons should oppose atvaton as the duse though the poe and ompetewth the atvaton parle o ts bdg ste hese eets wee n atobseved o expessed poassum hanels Fy esdue segmets deleted oinseted n the han" eteen the Ntemnal nactvaton atcle and thememane aeeate o so nactvaton (7) Extea potassum ons alsoslow nactvaton and speed eovey om nactvaton as expeted nact

vaton anno ou whle the poe oued by pemeant on ( ). heeesults suppor the baladhan" mehansm as a vald mode o potassumchanne nactaton

he ecepto ocuped by the Nemna natvaton patcle as t oudes the mouth o the potassm hae may de ao ad esdesn the shot ntacelula loop connectg tasmembane segments S4 and Sutageness o haged esdues ths oop to neuta, hydoph ones andmutatons o hydophobc esdues to aanne makedy edue ast potassumhanne nactvaton (0) Mutatons n ths loop also educe onductance andalte on eletty o the potaum anel ( hu th shot ntracel-ula loo may ontbute to omaton o the taelua mouth o the poeaong wth seuences n the ntaeua ed o the S 6 segment ad the S egon as desbed aove, ad may seve to om a ecepto o theamnotemnal nactvaton pace

Any w chapter, as we as any artce ctd In an w chaptermay purhased fom he Annual Reviews Pepints and Repns vie

177; 117 ema: [email protected]

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Remakable pogess has bee made i he pas evea yeas wad deniin the tructura eeet that are repe r the aic uct hetae-gated chae Beyd te ew iht it he tructure adfuct the ddua chane that hae een aed a cnaity uctia dei ha eered that a a ae chae atad permeabty prperte t be deried r ubte ariat n a cntructura thee. Th caty uct ered i the cructure r tae eg he S4 eent the eaed ructue theprer re the chae and he ute aai hei equecehch daatcay aer eectty, the ar catn eceptr e extacelua and tacelula pecn du a deet channeype, ad he cn echanitic ai r nactai iu adptau chae ee huh he rucura a actiai the chane dere Future ietiatin ui the preety aaiae ethd pren cheitry utaee uctia epei ad ecua

dei hud deeate the pay tuctua ai r he eetia unct the chae ad r the uctia dierece etee dieechanne type at eer hghe reluin Hwee a echantc undetadig thee prcee term protei tucture wi utiate requre deteat he threedea tructure a eer the i chaneal

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