Tr1In<workl Re<earctl Networl<

37IMl (2), Fort P.O., T';~.ndrum·6'JS 023, Kerala, Indi.

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Recent Re•. De.0'I. Biophys., 3(2004): 351·36215BN: 81-7895-130·4

Biophysical and biomedical

aspects of KCNE potassium
channel ancillary subunits
Yi Wanl, Ki Ho Park, looonarcio He....n••• SIIi·QónI Cal
an<! Fe<Ierico Sud
Univenity of r-..diti... and Dwo;otrr of!'le""" jene)I. RoI>ert Wood Johrnon
Medial Sctoool. Def>anmetll 01 ~ ...,; ~,. ~15 Hoes Uno
PiK.mw.Jy.!'lJ~.USA

Introduction
In 1988 Takumi ~nd col1c~g"eo. ide",ified ~ gene
encoding a predicted small peptide wilh a single
transmembl"ane domain 11]. When Ihe novel prolein
waS expre5sed in Xetloplls oocytes it produced a
moderate polassium currenl. resembling lhe slow
component of lhe cardiac delayed repolarizing

I
cum:nl. IK •• The new gene was nicknamed />linK. for
''minimal K' channcl" and for a long lime MinK
(KCNE1) waS lhoughl lO be able lO form channels on
115 own. [1 was only eighl ye3rs laler lhal il
wasdiscoveredlhat KCNEI was incapable lO form
c_
Wood
-.'Ropoi" roq.... Df fodm", S..... U........ .,..f Medo".. ".¡ D<l>IJ<tryof " .... I<fW)",_
J _ "'nl,,,," Sd>ooI.llrp""- ofPby."""t'I ".¡ aoopllYM<s' 6" 11<><> l .... "'_'''""1', Ni ous~
1

USA.E-m.oil..."fc@mndd¡.<du
potassium seleclive pore$ and !hal the CIlJft1lI seen in OOC)1e5 resutled from
wusmlbly ....i1h 5O!I1c: ~nous channel. Re«nlly. in an IlIempt 10 fiOO 1
partne1" for HERG.ihree KCNEI·related peptides,.,ere idenlifled in lhe human
~me [2), Since lhen. research inlo KCNE proteins has bttn rapidly
expanding. Now KCNEs are kno"'n lO span ihe euklryotic kingdom from
inver1ebnlles lO mammllls. lO form partnerships wilh diverse pore-forming
subunilS and lo uuse genetk disease. tlere. we review genelic, biophysical and
physiologkal aspecls oflhese fascinaling proleins.

KCNE genes across pbyla

Thus far. KCNE genes have bttn ickmified in the genome of marnmals
incllldillll hull'lllllS. amphibians (Xc...",.., loe>'u) &lid invn1cbn1e:s (e e/egun.s)
[1-5). The human sub-family is composed of KCNEl (MinK) thc: first KCNE
prol:cin lO be discoveml and foor more ~ ihat ",ere identified recenlly.
l1Ie X..nopUf family has four members iha! share homologiC'S with "CNEI,
KCNE) and KCNES. The nemalooe C. e/eguns has one member.1I11'S1. II is
likely lhat all KCNE pcplides descend from a COtlltllO" anceslor. Human
KCNE2 and KCNE4 uhibil significan! homology wilh ll>t N_lerminus and
lranslTlCmbrane dornain and C-terminus, .C$petl;.'ely. of MI'SI suggesting Ihal
they mighl be lhe resull of evolul;onary splieing.

KC E interadions wilh pore·rorming subunits

KCNE proteittS can ;nlefXI ,,'ith divC1'K pore-forming subonilS ofthe_
specie and of differcnl species 12, 6-21). More th:an 20 intcrac:tions llave bttn
discovered aOO probably morc w;ll be foond as oo. und~ing of these
proleins progresse5 (uble 1). In heart. KeNEI coassembles wilh KCNQl lO
form lhe channel underlying Ihe I~. eurrenl [6. 7]. In helerologolls expression
syslcms lhe olher KCNEs llSSOciale wilh. and modulale KCNQI. Some
complcxes intludin¡ KCNE2IKCNQl and ,..rNE1/,..rNQI prob8bly opcnl1e in
pancreas lOO colon whcreas il is slill undear whether KCNE4 and KCNES
combine ",ilh KCNQl ", viro 116. n.23). HiSlorkally, 1M ~h fOl' new
KCNE proteins ..~ underuken in order lo find a partner fOl' HERG. a dlannel
!hal proctuccs the rapid componenl (1",) of the dela)ed "enuicular repoIarizing
CUlTnII 124-26]. This cffon led lo the discmCl)' of three new KCNE pcptides
and me of lhem. KCNE2. "'aS proposcd lO be the missina: subwlil (2]. An
iOOependenl group idenlified KCNES 15]. ll1e hYPolhesis Ihll KCNE2 i5' beta
subun;t rOO' HERG ....-as inilially IIC«pled W;lh skeplicism bul intrcuingly
evidcncc: has beer1 atcUmulaling in suppon of Ihis not.;on [27-30]. ThU5.
KCNE2IHERG eomplexe5 resemble nalive 1", thaoncls in Iheir galing.
condocunce and phannatoloJlY [2,31·)5]. We5lem blol aod RT-PCR aoalysis
reveals KCNE2 exprasion in humao. horx. dog and tal venlrid~ [36.37).
Tlbl~ 1. Lisl ofrcportcd ¡nlcr(IClions oclwocn huma" KeNE prolcins and por~~formin8
~l>units.

"CN!';I K~O K~" "CNFA "CNF-S

KCNQl KCNQl KCNQI

HERO itERO
''''''' '''''''
IlERG KvU

Kv).! IICNI KV).1 KvD

Kv).2 ,,= Kv).•

~. Kv2.1
K>"4.2 K>"4.l

'''''''
'''''''
K'ISI

Missense mutations in Ihe KCNE2 gene are carrie<l by individuals affected by

cardiac disease [2, 31. 32, 34. 38-40). KCNE2 however might not be lhe only
bela subunil for HERG in heart. Not only KCNEI can associate with this
ehannel in mammalian eeUs (without allering its functional charaetcristics);
more importantly. in membmnes from equine atrium and vemricle KCNE I and
HERG onhologs coimmunoprccipitate [8, 37[. Like its relalives. KeNE3 boasls
a wide speetNm of partnerships. Jt fonns a eomplex with Kv3.4 in skeletal
musele thal is expe<:ted to se! the rcsting pCltential of musele "clls [111. In mt
brain. KCNE3 endows the funetion ofKv2.1 and Kv3.1 [181. It is likely tha!
KeNEs were bom as nervous proleins and that laler they evolved to funetion in
other tissues. The original neuronal vocalion of KeNEs is emphasized by C.
ell:s,ms MPS 1. This prOlein is expressed in Ihe nemalode nervous system where
it associales wilh diverse pore-fonning subunils ineluding KVSI. a "ollage
galed K' ehannel. Disruption of complexes re.ulting from the coassembly of
MPSl and KVSl by RNAi is associaled with several neuronal defccts
suggesling thal MPS 1 is required for lhe normal funetion of several neuronal
types. through modulal;on ofvoltage·dependenl potassium currenls [4]. KeNE
proleins have lhe ability to establish interactions that are not physiologicaL For
instance human KeNE lean assemblc with endogenous pore-forming subunit in
'"
Xt~ ooq1es. probably KCI\QI orthoIOJs and so too. encSogmoos XCnoptd
K~EJ inta'aCtS ""ilh hercrologOllliIy Cll"prnKd HEIlO (l. 31- On Ihc othcr
hMd. lhen: is evi<knc:c that KCNE prOkim can savc nwtliplc dwmcls in
...¡", li~_ We ...~~ a1rndy lnf:fIlioncd thaI. in horse Man KCNEI usoc:iali~S
wnh KCNQI and HEIlG. in rat lnin KCNE2 mdows K..2.1 and KvJ.! and in
e tltgans in addition 10 KVSI. MPSl partners .. ílh multipk pore-fonnin¡
sub\lnil$ .... hosc idcntily has nDI bcnI ucertIlined ye!. lbe physiolOlical
ronsequmces of KCNE promiscui'y should not ~ urwkn:s!imaled bc<:lIUIC
¡enelic mUlattons in lhcse small genes might ha>'c lhe potcntial rOl' lading 10
dimlption ofmuhiplc CUrrm\5 simuhl\llCOllSly.

Biophysical aftributes of KCNE proteins

'rhe amino-acid se:quences of KeNE mcmbe., of lhe human-subfamily are
displaycd in figure 1. llydropalhy analysis pr«!i"s KeNEs lo be membranc
proleíns with an external N-lcrminus and a single mcmhrane spat",ing domain
(TMO). a nmi.m validalcd by several lines of cvidencc. Thc e:<traccl1ular
orientalían of lhe N-ICl'minus has bttn ti5C3scd by ')"Ioimmunochemical
rnclhods and by lhe obscrvalioo ¡ha! matu~ "CNE protcins are fully
¡l)cosylated (2. 4. 17.41). The role of glyOOlSyllli(lfl for "CNE function
remaim elusi~"e hown<er. [)espile lhe faet Ihal 111 "CNE members e:<hibit one
or _ N-glycosylltion scquences in !he N-lerminu5 (figure 1). disnlption of

~-----§~... ~~---~-_....
~"";;;;""'" _c-G.i-- ",AO "'

,
"'-
....
_h l'"''
·_A''''~------ _
~ ~ f

........... " I " l n n l R a ~

•"
______ 'rVIlOI'~....eO, ._IAIEg ......-.:n.
----------YU\llUO_.'_''''''''' •••
------.,----_.-- - --... -------------------
....,. ~ •.....,.t.e_.""".ou••_ ... '~n.

- .-- - --- ~f'O'.·· ""_... "Q..............¡¡O;¡. . . v-

"" l~

~1t:..rt l. r.po* >tq.'lKtl f.... IM r•• ;I) .r J.:c...r... T1lc tÑ.lrttrIond bl...
c:oloIS il>llieak idmIiaL ~ ) somib" ",...u.!) 5UIIl'" =pecIi.-e!)'
S!:qo.ama oI~ ....., oiIlall..d by CJusuJ\\ ~IS ibl* • hnp~''1I1'S"'
pbiJ.ibcp.f'!czi-tHn!np._ _ .p/"¡lIce-NPSAlIIJ'S"_dllSUho ,hanl.
1l'''I'hysioal .nd biomc<lioal asp«" of .-eNE ""....mm cllan",,1 .",,¡IIM}' subu"'" 355

Ihcse siles can be ach;eved w;lhout nOliceable effect5 [39. 42J. Small KCNEl
peptides C<)IYeSponding to the TMD ofKCNEl have bcen synlhesized. inoorporated
into phospholipid membranes and analyzed by Fourier lransfonn and CD
spectrosropy [43]. As expected. me peplide adOplS a predominamly alpha·helical
conformat;on, a finding consistenl with lhe proposed SlnlCluralflopological model.
KCNEs broadly affecl Ihe function of their panncrs including lrafficking,
galing. penneation and pharmacology. Sub,tantial evidence suppons the notion
Ihat lhe molecular determinants for KCNE comrol of channel funClion are
grouped in the transmembrane domain (TMD) and in adjacenl portions ofme C-
terminus. which in fact. are h;ghly conserved (f'gure 1). Takumi and colleagues
expressed a series of rat KCNEl mutant deletions in X<,no(!us oocyles [42].
Deletion of residues 10-39 (which contain the glycosylation sites) could he
aehieved wilhout noticeable effects. Eventually. Ihey could construct a minimal
KCNEl peplide of63 residues Ihat included residue, 1-9 and 40-94 ",aimaining
the transmembrane ""g",ent (A4~-167). Several residues lacaled in Ihe KCNE 1
C-terminus Can alter the funet;on of the complexo For instaf\Ce, a conserved
serine at position 68 confers susceplibility lO telraethylammonium. a classic K'
channel blocke, [44]. Two mutations (S74L and D76N) found in patiell1s
affecled by cardiac armythmia reducc Ihe unitary current more Ihan by 50 ~o
[4~. 461. Melman and colleagues constructed a series of chime"... between
KCNEl and KCNE3. and identified three residue•• lacated in equivalem
posilions in the lransmembrane span oflhe two protein. that modulate KCNQl
activation [47). In a subsequem study the same group showed that Ihe prcciscly
spacing ofthe central amino acid oflhe triplel is sufficienllo give the KCNEl
or KCNE3 p1tenolype [48]. lltese findings argue that KCNEI and KCNE]
occupy the same posilion in the complex and that Ihey "omrol KCNQl galing
through conservw me<:hanisms. MUlalions of two residues conserved among
KCNE1. KCNE2 and KCNE3 affect Ihe FunClion of complexes form~'<l with the
natural panners. KCNQI, HERG and Kv3.4 respectively 149]. Moreover, mixw
complex,," formed with ead! KCNE mUlant and the olher alpha-subunils also
exhibit alterw charat:terislics [49]. The exiSlente of COmntOn mechanisms
seems 10 80 beyond specie boundaries. KCNE2 and Kv4.2 subunits coassemble
in helerologous expression systems [13). Based on the analogy of Ihis "hannel
complex with e elegans MPSI/KVSI, Bianchi and oolleagues assessed the
effe<;t of expressing hybrid ehannels Formed wilh KCNE2 and C. elegans KVSI
and wilh C. eiegans MPSI and human Kv4.2 [4). Interestingly. not only bolh
KCNEs a1ten"d the anributes of pore-forming subunits dislanl in Ihe
evolutionary sca!c bUI also Ihcy modulaled the ehannels similarly. Thus. general
stru"lUral and fUtlClional principies secrn lO be eonserved among KCNEs of
diverse species.
KCNQI subunits are chara"tcri~e<l by fast aClivation kineties and small
unitary conductance (-4 pS as asscssed by noise-variance analysis) [45, 50. 51].
", Yi WOIlJl "a/.

Co-expressioo with KCNQl dramalically ahcrs KCNQl chamelerislics and

confers auribUICS Iha! re<:apilulate lhose of "a1i"" J~, currcms [6. 7]. Thus.
KCNE! slows down KCNQI actival;on kinetics _1 O-fold. shifts by 20 mV Ihe
threshold for sleady-slale aClivalion. alters ehan"el pharmacoJogy and ¡ncreases
4·fold ¡he un;tary curren!. These strang cITect. poin! out thal KeNE! may
inlcrael quite imimatcly with KCNQI. protmbly with lhe chan"e!'. COfe. By
usíng cysleine-scanning mutagenesis. Tai and Goldstein identitied lwo adjacem
residues located in lhe TMD of KeNE1 thal can be reached anly by extemal or
intemal cadmium respe<:lively suggesling lhal Ihese ami"o acids are ex~ lO
lhe ion-<;:onduction pathway (3 nOlion indire<:lly supported by lhe observat;on
lhal KCNE I increases the unitary curren1, figure 1) [51J. Alternative hypolhesis
conceming KCNEI location "'ere aloo proposed, until recenlly Melman and
collabonl1ors have provided direct evidence of physical ¡nteraclion of KCNE 1
dornains "'ilh Ihe KCNQl pore [53-55J. Potassiurn channels are lelramers of
four identical subunils arranged to foon a eenlral pore and the number of KCNE
subunits per telramer has been a eontro\'ersial issue [56-60J. Recenlly. Chen and
colleagues have used clegant slrategies lO provide direcl as~ssmenl of Ihis
number [61J. By using a KCNQl mutanl highly sensilive to eharybdotoxin. a
modified KCNEI and landem conslrucls. 1hcse aUlhors ",ere able lo compare Ihe
number of channels nalurally assembled of monomer subunils wilh those of
linked subunils Ihal forced fonnation ofchannels with definile sloiehiometries.

Flj(ure Z, Propos~d srrucluN' Jor K' clumn<!l compleus CQnlaining KCNE subunilJ. Four
i<lentical K' chan""l ~ubunit~ (po:aeh) and t,.-o KCNE subunits (bluc) form a single.
contra] ion-eunduction path,.-ay. Note the prescnce uF large earbohydrales al1acl>cd to ¡l>c
KCNE pcptide (green branche~). In KCNE2/1lERG channcl$. these I:roup~ $hicld ¡he
SMX ICceptor and thus proteet 1he complex fmm lhe inhibimry elfeet of the drug. ¡",el
mp ,iew oflhe complexo Thc grttn sllaoo,.-s represent lhe oligosacchari<ks groups.
1"0....)·...,.. .... boom«b::al aopcctJorKCNE _ .... d ••nn<l_,llo<y............ 357

As a rnull5 U- &lllhors eonclude mat theno an: 1,"'0 KCNEI pcr t~"'1tKl"
r;onfinnin¡ a prnious study camal out '"ith flIt KCNEI subtJnll.$ in X~nopw
ooqtcs (fi¡~ 2) In). Funhcr $ludies "'ill bol: required 10 asceruoin ..-Iw:t:hcr thf:
_ stoichiometry is opectal fOl" OIhcr K' dLannds lIw rontain KeNEs.

KC Es can cause congenilal and acquired cardiac

disease
Atteored ionic f1u~cs may impai, ~'enlricular repolariution leading lhe onsel
of a grouP of di~ Ihal can manifest thf:mselvcs in dlhcr conllC'nital and
acquired form: the Long QT 5)'Tld~ (LQTs) 162. 63]. BOIh Ko.'EI and
KCNE:2 modul~te repolarizing K' currcnls chrough lllisembling ",ith KCNQl
.00 HERG aOO mUlalions in lhese genes can bol: proorrhythmic [2. 38. 46. 641.
KCNEI Slrongl), allen KCNQI chal'llCleristics Ihel'<'fore ehannels formed from
lhe eoassembl)' of mulanl sulJ.unils are expceled lO e.~hibil Slrongl), reduced
fuoction. In fad. KCNEI mUlanl5 have ~n mainl)' associaled "'ilh 1"'0
familial fonns of LQTs: Romaroo Ward (aulosomal dominam) and Jen-ell and
l ...ge-Nielscn S}'ndrome (aUlosomal recessive) [46. 64. 651, Since LQTs
predisposcs lO l~h:~.1 .....)1hm'U- chis disea.sc is rllrC: in congenital form.
Aequired LQT is more cornmon afien rnulling as a sido: dTect of block of
IIERG ehannels b) drup of divC'f'SC Ihcrapeulical ctasscs. 'The causes fOl"
acql.llml LQTs ha\'e been unel,..,. until thf: diSCO\C'T)' of KCNE2 ...d the
invnti¡ation into HERG stnK1ure ha~'e shed ali¡hl inlo thf: moIe<:ular bases for
chis di5Of'der. Unlike thf: IIIaJOI"ily of \Oltage-pled K' channels.. HERG has
_ i e residues in Ihe inner Clvity thal C1lrt ac1 to l",p SC\enal moleculcs [66].
HERG unique SlJUCl.ure is responsible ooly in pa11 for thls pathology ho-.'C\'eI'.
Se>'enal 0r\Ji' inhibil 1", from the e-'<Icmal sidc oflhe membranoe and further.
palicnlS llIal dC'o'elop LQTI exhibit slightly 10nllel' QT inlervals Ihan IIvenoge
undersa:Jñng genetic prediSfKlSition (67. 68]. The m}'ocardium has 11
repoi<...izing res,c,......,. !hlll il "~ec» ""pllCity lo dr«1 on:I".ly llOO rllpid
repollll'ization ..ia IlOnnll mechanisms [69]. Genelic faclOn¡ lhal chronically
dcpl~l~ lhe rese...e may predispose 10 acquired-LQTI by leavinll lhc
myocardium incapable lO SUSlain funher cardiac insulls. Fi..c misscnsc
mulalions and a single-nucleotide polymorphism in lhe KCNE21lcnc ha..c b<.~"
identified in diverse groops of iOOi..iduals afTe<:ted by drug-induced LQTs [2.
32.381. Funclionally. lhe mulants d~rcase IllaCrosl:opic Hf.RG current by 36-
50"1. in hcterologou~ opression systems. Since lhese efTects are rclali~'ely mildo
!he muW1ts an: likely lO pn:dispose 10 LQTs thrnugh dcple1in¡ the: repoIarizing
I'CSCO'C. This tbol:ory uplaim ",hy LQTs lll'05C afiel' trellunenl ...ilh drugs l1w
can further inhibit 1", CUrnTll5. KCNE2 can also induce LQTs by increasing thf:
affilllty 10 11 spccific dru¡. A Slll8le-nuc:leoxidc poI}-morphism. TlA·KCNE2. '"'aS
found In !he gellOl'~ or a palicnt thaI ohibited ..mal QT proIongaIion aflel'
)5,

!leíng ¡reated wllh the anlibiOlic sulfamethoxazole (SMX) [38). Electro-

physiological sludies showed lhal channels formed wjlh TSA were al leasl 4-fold
more scnsilivc 10 scrological levels of SMX than ",¡Id typc channel. and these
findings provided a din..'C1 cxplanalÍon for the clínical case. par\¡ and oolleagues
foumllhal HERG channcls alone are highly susceptible lO SMX and lhal KCNE2
exc". a eardio-protective cfreel against this drug [391. They showed thal imperfecl
glyoosylation (lhe mutal;oo OCcurs in a glycosylation sile) is lhe primary CIIuse ro.-
SMX high-aflínity block and thal lhe polymorphism increases drug susceptibility
lhrough slrueturnl modificalions in lhe channel complex. These authors argue tha!
lhe con!;e(jucnces of lhe peculiar structural fealures of KCNE2JHERG charmels
could be significan! bccause individuals carrying T8A migh! be al ,isk of
arrhythmia when tn:ale<! no! only wilh SMX hut also with Qthcr drugs.

Conclusions
Accessory subunilS are a fundamental feature of polassium channels lhal
detenninc lraffieking IQ the plasma mcmbrane. localion, abundanee. sensilivity
to slimulaliQn and phannaco\ogy. Thc KCNE family is eme.ging as a general
e1ass of ancillary subunils of vollage_galed K' channels. lssues that will receive
auention in thc nea. future an: likely IQ revolve around KCNE role in
IralT,,:king. and IXhe. relalcd eel1ular funcl;ons. Othcr imponam topies inelude
the idcntificalion ofKCNE pcplidcs funetiQning in eukal)'oles as well in the IWO
othcr kingdoms. TIte idcnlifiealion/eharaeteriutiQn Qf new channel complexes
is an ongoing eITorl. In this resP'C"t. the use of simple animal syslcms seemS a
reasonable slr3legy lO overCQtnC lhe limótations of highe. organisms withQut
losing the abilily lO work in a lruc physiological ,omext

Acknowlcdgements
We manks Cínxia Sest; wilh help with me graphics. lllis w<Hi< was supponcd
by a NIH CtWlt ROIGM68581·01 and al> AHA grant SDC H(I23S470T te FS.

Refcrcnccs
l. Takumi. T.. 11, Oltkubo. and S. NakanishL Clt;"úng "1 a mem/>raIW pro";n ,ltal
induus" gliw.' "nllage-gated ('(}/a<siWflcurre"'. Scicnce. 1988.1~1( 4881): p. I (I·U-5.
2. AbbolL G.. et al.• MiRPI forms IK, potassium c1um,,"¡. with IIF..RG and is lWJlX:ialed
wüh c(JN}ioc a"hylhmw. Cct!. 1999. 97: p. 17~·87.
3, Ananthamm. A., el al .• RNA /",ufen""" Re"""/. 100, EndtJge1tQ1l.$ Xenopll.$ MinK_
ff/all?d l'eptidts Go.-.m Mammaliall K+ Ch<Jmw:1 Funclj()lt in Ooq·te &presskm
.~Iudie•. J filo) Chem. 2003. 278( 14): p, 11739--4~.
4, Uianchi. Lo. el al.• A poIassi"'" chtm",,/_MiRP complex "onlrol. IIeurosenwrylun<:titm
in C""nor/ltJbditis e/eJiia",. J Uiol Chem. 2003, 278( 14): p, 124 1S-24.
S. l'iox;';~ M. el al.• KCNEI-Iiú ~'" " dekttd in A.\llfE cont<gUOus 8'''' .<yrIdrtJmt:
;Jell/ifl(:(J(i(¡r, and citaracltri:a1lOtl ,,/ /he """'-'" Irom%gues. Genomics. 1999,60:"
 251-7.
6. Ilathanin. J.. el al.. K(I )LQTI and lIt: (mi"K) prou;", tu""';'JI" 10 larm ,1If I(KI)
<:<udi« ¡JOIQMI_ CJIIT"'" NlIIlIR'. 19%, .384(66l.:M): p. 7I-SO.
7. s.cuinetlL \l.. el .. ~ C_ _ bIy of KwLQTI ,.,.¡ MIIIK (IIK)",.-_ fOIl ¡o,.
~ IAspouus,_ ~ I SlII\lI'C. 1996. Jll.l P. 80-3
l. McDonlld. T.• el .... A MIIIK-I/ERO COlltp/u rrKtJolrl ,lo,. cwdl<M: poI(U:I''''''
c~rrr'" 11',. Nalure. 19'97. JlllJ: p. 2111·112.
9. Lcwis, A.• lA M<:Cro~san. (Uld G.W, Ahootl. M",K, Milll' 1, u"", \/IR/'} dl>'r,sl/)'
Kd.1 aM A';1 poItJ.fIU¡1// cloanntl gui'ng J Ríol Chelo .• 20M. 279(11): p. 7184-112.
10. TIllCL N~ d a1_ M·"pr KCNQ1-KC\QJ ptIfOM'_ cIoawwls ...... -'wJClIflI by'lo,.
KC\ El ",,,-•. FEBS I.tll. 2000 ol8O(2-3>o p. 13741
11 TIllCL N_ d al. KC.\f:1 COIlfrn bodpotmd nil7'r1fl d""nctmllic:a lO"'" e<mIioc
KC\QI poN=r_ c/"m_I, Emho J. 2000. 19(231; p. 6J2ó-30.
12. Yu. ti.• el al.• MmK."'''Jlrd prptidr 1. u M/a IIlb"""lar'M IICV '" f'h<¡1/I1r/ I"b"""
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H Cumu>. M.• el al.. ,j Molu"lo, baus fix CIl,d,IJC o"hj'lhmio. IIf:RG ","IiJ,ioos
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'''' y,Wans"ol.

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