1999 evolution and diversity of mammalian sodium channel genes.pdf

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a ) i n t he hum a n a nd m ous e genes (P l um m er et al., 1998),om pa r e d w i t h a n a v e ra g e v a l ue of 86% f or h u m a n a n d

mouse coding seq uences (Ma ka lowski et al., 1996). P hosphor-lat ion of residues w ithin t he cytoplasmic loops is known toa v e di st i nct effect s on t he kinet i cs of di ffer ent cha nnel sMurphy et al., 1996; Sm ith a nd G oldin, 1996; Frohnw ieser et l . , 1997).

HumanSCN6A and MouseScn7a Appear

to be Orthologs of a Single Gene

SC N 6 A a n d SC N 7 A wer e gi ven di ffer ent gene s y m b ol swhen they were mapped in human and mouse, respectively

George et al., 1994; Potts et al., 1993). How ever, the un usua lroperties t hey sha re a nd the la ck of evidence for t wo genes

within any one species suggest that SC N 6 A a nd SC N 7 A a r ec t ua l l y t he hum a n a nd m ous e or t hol ogs of a s i ngl e l ocus .

SC N 6 A i n hum a n a nd SC N 7 A in mouse ar e expressed in both

eur ona l a nd nonneur ona l t i s s ues , unl i ke t he ot her c ha n-els. Neither SC N 6 A nor SC N 7 A generates sodium currents

when the cDNAs are expressed in Xenopus oocytes (Felipe et l . , 1994; Akopia n et al ., 1997). The protein sequence of

SC N 6 A a n d SC N 7 A diverges from the other family membersby 50%, including cha nges in tw o critical d omains a ffectingvoltage sensitivity and ion selectivity (Gautron et al., 1992;George et al., 1992; Felipe et al., 1994; Akopian et al., 1997).The 68% amino acid identity of human SC N 6 A a nd m ous eSC N 7 A is consistent with the expecta tion for orthologousgenes (Felipe et al., 1994). However, this gene appears to bed iv er g in g m u ch m or e r a p id ly t h a n t h e ot h e r ␣ subunits.Human SCN8A and mouse SCN8A, for example, are 98.5%identical in a mino a cid sequence (Plummer et al., 1998).

Alternative Splicing of Neuronal SodiumChannels

Three si tes of a l ternat ive splicing furt her increase t he di-versity of neuronal sodium channel isoforms in mammaliantissues. These isoforms were first identified as cDNAs andlater explained by splicing mechanisms. The a lternat ive ex-ons 5N a nd 5A ar e separ at ed by less tha n 100 bp and encode

segments S 3 and S 4 of domain I in SC N 2 A, SC N 3 A, SC N 8 A,

a n d S C N 9 A ( S a r a o et a l . , 1991; G usta fson et a l . , 1993;Belcher et al ., 1995; Plummer et al ., 1997). Expr ession ofexon 5N pr edom i na t es i n t he neona t a l per i od, a nd exon A

FIG. 2. The ma mma lia n s odium cha nnel ␣ subunit genes are located in four paralogous chromosome regions. The ancestral chordate

enome is proposed to contain one copy of each gene listed a t the left . D uplicat ion events generated four para logous chromosome segments.

ndependent duplication, deletion, and translocation events subsequently altered the gene content of the paralogous segments and dividedhe region containing H O X A a nd SCN5A into three unlinked segments. The chromosomal locations of the corresponding mouse linkageroups are provided in Table 1. G enes are listed in alpha betical order because t heir physical order is not completely known. G ene symbols:

QP, a qua porin; C O L A , collagen ␣; C A C N B , calcium channel ␤; E R B B , a via n eryt hrobla s t ic leukemia vira l oncogene homolog; E V X ,ven-skipped homeobox; HOX, antennapedia -like homeobox; I T G A , integrin ␣; I T G B , integrin ␤; K R T , kera t in gene clust er ; N E U R O D ,

eurogenic differentia tion; N F E , nuclear factor erythroid; RAR, retinoic acid receptor; S C N A , sodium cha nnel ␣ subunit ; SLC4, solute carrieramily 4, anion exchanger; WNT, wingless -related. L inkage dat a from OMIM (Online Mendelian Inherita nce in Ma n, ht tp://ww w.ncbi.nlm.ih.gov/omim); TTX, tet rodotoxin; S , sensit ive, R, r esista nt .

325E V OL U TI O N O F TH E S O D I U M C H AN N E L G E N E F AM I L Y



redominat es in th e a dult . E xon 5N a nd exon 5A differ by aonsistent amino acid difference: the residue is uncharged inhe neona t a l i s ofor m a nd nega t i v el y c ha r ged i n t he a dul tsoform (Fig. 1, a rrow). The functiona l consequence of t hisonserved a mino acid substi tution is not known.

The alternative exons 18N and 18A of SC N 8 A encode the3 a nd S 4 s egm ent s of dom a i n I I I (P l um m er et al., 1997).

These exons share several features with exons 5A and 5N.oth pa irs of exons encode the S3 an d S4 segments of domain

II. Both pairs of exons are developmentally regulated withxon N expressed in ea rly d evelopment a nd exon A expressedn a dult . The genomic orga nizat ion of both pairs of exons isi m i l a r , wi t h t he ups t r ea m , neona t a l exon s epa r a t ed fr omhe adult exon by a small intron of 100 to 500 bp. Surpris-ngly, exon 18N of SC N 8 A contains a stop codon that wouldesult in synt hesis of a truncat ed tw o-domain protein (Plum-

m er et al., 1997). The fun ction of such a tr unca ted protein isnclear. Similar transcripts of SC N 1 A a nd SC N 8 A contain-

ng stop codons in d omain II I h ave been isolat ed from ast ro-ytes and neuroblastoma cells (Oh and Waxman, 1998).

Finally, alternative splicing in the first cytoplasmic loop ofSC N 1 A a nd SC N 8 A gener a t es t w o t r a ns c r ipt s t ha t di ffer b y10 amino a cids, due t o uti l ization of a l ternat ive splice donorsites in exon 10B (Schaller et al., 1992; Dietrich et al., 1998;Plummer et al ., 1998). In contra st to the neuron-specifi cgenes , no a l t er na t e t r a ns c r i pt s of SC N 4 A or SC N 5 A h a v ebeen identified.

Effects of Interaction with AuxiliarySubunits

Additiona l functiona l diversity of sodium cha nnels is gen-erated by interaction with the auxil iary subunits ␤1 a nd ␤2,encoded by the genes SC N 1 B a nd SC N 2 B (Ta ble 1). B oth ␤1a nd ␤2 cont a i n a s ingl e t r a ns m em br a ne s egm ent , a n i nt r a -cellular C-terminal domain, a nd a n extra cellular N-terminaldomain with an immunoglobulin-like (Ig) fold (Fig. 1), buttheir amino acid sequences are not related.

SC N 1 B is expressed in neurons, skeleta l muscle, a nd ca r-dia c muscle (Isom et al., 1992). Coexpression of SC N 1 B w i t h␣ s ubuni t s fr om b r a i n a nd s kel et a l m us cl e a cceler a t es t heki net i c s of c ha nnel a c t i v a t i on a nd i na c t i v a t i on, a l t er s t hevolta ge dependence of ina ctivat ion, an d increases peak cur-rent (Isom et al., 1992; Patton et al., 1994). Mut a tion of th e Igfold a bolished t he effect of SC N 1 B on ␣ subunit ina ctivat ion(McCormick et al., 1998; Wa lla ce et al., 1998). Coexpressionof SC N 1 B w i t h t h e c a r d ia c ␣ subunit SC N 5 A increases so-dium current but does not al ter channel kinetics (Qu et al.,

1995).SC N 2 B is expressed only in the nervous system (Wollner et

al ., 1987; Isom et al., 1995) and is covalently bound to the ␣

subunit by disulfide bonds (Messner and Catterall , 1985).SC N 2 B also conta ins a n extra cellular Ig fold w ith h omologyto the neural cell adhesion molecule contactin (Isom et al.,

1995) and may play a role in response to extracellular sig-nals. Coexpression of SC N 2 B alters the voltage dependenceand kinetics of inactivation of ␣ subunits and enhances lo-calizat ion in t he cell membra ne (Isom et al., 1995).

SodiumChannel Mutations and Inherited Disease

F our s odium c ha n nel ␣ s u b u n it s a n d o n e ␤ s u b u n it h a v eb ee n a s s oc ia t e d w i t h i n h er i t e d d i s ea s e i n h u m a n p a t i e n t sa n d m ous e m ut a nt s (Ta b l e 3 ). The s i t e-di r ect ed m ut a t i onof S CN 2 A, G AL8 79 -8 81 Q3, r es ul t s i n s l ow ed c ha nn el i n-a c t i v a t i o n ( K o n t i s a n d G o l d i n , 1 9 9 3 ) , a n d e x p r e s s i o n i n

TABLE 2

Conservation of Various Protein Domains i n So-dium C hannels from Four Paralogous ChromosomeSegments

SCN8A domain

%a mino a cid s equence ident it y t o

SCN 2A SCN 4A SCN 5A

D oma in I 79% 75% 69%C y t opla smic loop I /I I 51% L ow 42%

D oma in I I 93% 89% 80%C y t opla smic loop I I /I I I 65% 41% L ow D oma in I I I a nd I V 86% 84% 81%

Note. P e r ce n t a g e a m i n o a c id s eq u e nce i d en t i t y w a s ca l cu l a t edus ing t he B ESTFI T progra m in t he GCG pa cka ge. L ow , dif ferentnumbers of exons a nd high degree of divergence ma ke a lignmentu n r el ia b l e. G e n B a n k c it a t i o n s: h u m a n S C N 8 A , AF049617; r a t

Scn2a, X03639; human SCN4A, L04236; human SCN5A, M77235.

FIG. 3. P hylogenet ic rela t ions hip of ma mma lia n volt a ge-ga t edodium cha nnel ␣ subunit genes. Pr otein sequences from rodent a nd

Drosophila sodium channel genes were aligned using CLUSTAL W

ersion 1.6 softwa re (Thompson et al. , 1994). The aligned regiononta ins 1154 a mino a cids (approximately 2

3 of the total) correspond-ng to rat Scn1a residues 105–273, 329–423, 763–992, and 1215–874 (GenB an k Accession N o. X03638). The diver gent portions of t he

N-t ermina l region, C-t ermina l region, a nd cyt opla s mic loops t ha t

ould not be aligned were not included in the analysis. The alignedequences w ere a na lyzed w it h t he P R OTP A R S progra m (prot einequence pa rsimony meth od) from P HYL IP version 3.5 (ht tp://evo-ution.genet ics.wa shing ton.edu/phylip.ht ml). The numbers a t nodes

re boot s t ra p va lues for 100 replica t es of t he pa rs imony a na lys is .enBank accession numbers: rat Scn1a, X03638; rat Scn2a, X03639;

a t Scn3a, Y00766; r at Scn4a, M26643; ra t Scn5a, M27902; ra tcn7a, Y09164; mouse Scn8a, AF049617; ra t Scn9a U79568; rat

cn10a, U 53833; ra t Scn11a, AF059030; Drosophila P ar a, M32078;

Drosophila DSC1, X14394-8. The analysis was carried out with theodent s equences beca us e s equence is not a va ila ble for t he huma n

enes SCN1A, SCN3A, a nd SCN11A. The chromosoma l locationshown in the figure are for the human orthologs (Table 1), becauseeveral of the rat genes have not been mapped to chromosomes.

26 P L U M M E R A N D M E I S L E R



r a n s g e n ic m i ce r e s u l t s i n f oca l m ot o r a b n or m a l i t i es a n de iz u r e s ( K ea r n e y , J . A. , P l u m m er , N . W. , S m i t h , M . R . ,

K a pur , J . , G oldi n, A. L. , a nd M ei s l er , M . H . , m a nus c r i pt i nr ep a r a t i on ). H u m a n d i s ea s e m u t a t i on s w e r e fi r s t d i s co v-r ed i n S C N 4 A (P t a c ek et al ., 1991; Rojas et al ., 1991). Aa r ge s er i es of a l l el i c S C N 4 A m u t a t i on s h a v e b ee n i d e n t i -ed i n pa t i ent s wi t h m us c l e di s ea s e a nd func t i ona l l y c ha r -c t er i zed (Bul m a n, 1 9 9 7 ; Ca nnon, 1 9 9 7 ). Inher i t ed m ut a -ons i n S C N 5 A w e r e f o u n d i n p a t i e n t s w i t h t h e L o n g -Q T

y n d r o m e t y p e 3 , a d o m i n a n t l y i n h e r i t e d d i s e a s e c h a r a c -er i zed b y pr ol onged c a r di a c a c t i on pot ent i a l s (Bennet t et

l . , 1995; Wang e t a l . , 1 9 9 5 ). S pont a neous a l l el i c m ut a -

i o n s o f t h e m o u s e S C N 8 A c h a n n e l r e s u l t i n a v a r i e t y o feur ol ogi c a l a b nor m a l i t i es i nc l udi ng c hr oni c a t a xi a , dy s -

o n ia , a n d l et h a l p a r a l y s i s ( Me is l er et al ., 1997).M os t of t he m ut a t i ons i n SC N 4 A a nd SC N 5 A result in

l owed cha nnel i na c t iv a t i on a nd exhi bi t dom i na nt i nher i -ance (Table 3). These can be considered “gain of function”

muta tions since the mut an t protein ha s functiona l propertieshat differ from those of the wildtype. At the cellular level ,he dom i na nt phenot y pe i n t hes e het er ozy got es ca n b e ex-l a i ned b y t he per s i s t ent c ur r ent gener a t ed b y t he m ut a nthannels even in the presence of normal channel proteins. Inont r a s t , t he m i s sens e m ut a t i on i n S CN 8 A i s r eces si velynherited, and heterozygotes are unaffected. Since this mu-

a t i on i ncr ea s es t he degr ee of depol a r i za t i on r eq uir ed forhannel opening, in heterozygous cells the wildtype channels

will continue to open in response to a ppropriate depolariza -on a nd ma inta in n ormal responsiveness. The recessive in-er i t a nc e of nul l m ut a t i ons i n S CN 8 A dem ons t r a t es t ha t0%of normal activity of this channel is sufficient for normalhysiological function.

The fir s t m ut a t i on i n a s odi um c ha nnel ␤ subunit gene,SC N 1 B, was recently identified in a human family with gen-

ralized epilepsy with febrile seizures plus (GEFSϩ), a formf childhood epilepsy (Wa llace et al ., 1998). I n functionalssa ys, the cysteine to glycine muta tion appears to inactivat ehe ␤ subunit , resulting in slowed ina ctivat ion of ␣ subunits.

Volta ge-gat ed sodium chan nels a re a lso of m edical signif-can ce as ta rgets for na tura l neurotoxins an d synthetic pha r-

macological compounds including anti-convulsant drugs, an-st het i cs , a nd neur opr ot ect i v e dr ugs t ha t a m el ior a t e t he

effec t s of s t r oke (Ta y l or a nd N a r a s i m ha n, 1 9 9 7 ; R a gs da l ea nd Avoli, 1998).

OverlappingPhenotypes of Mutations in Different

Neuronal Ion Channels

The recent identification of disease mutations has revealedoverlapping phenotypes resulting from mutations in differ-ent voltage-gat ed chann els. E pilepsy a nd seizures ha ve beenassociated with mutations in six genes: a sodium channel ␣

subunit , a sodium channel ␤ subunit , a potassium channel ␣subunit , and the calcium chann el ␣, ␤, a n d ␥ subunits (Table

4 ). Inher i t ed a t a xi a ha s b een a s s oc i a t ed wi t h m ut a t i ons i nfour genes: a sodium channel ␣ s ub uni t a nd t hr ee c a l ci umchannel subunits. Mice with mutations in the ␣ subunits ofc a l c i um a nd s odi um c ha nnel s exhi b i t a s i m i l a r a t a xi c ga i t(Fletcher et al ., 1996; Kohrman et al ., 1996). The clinicalsimilari t ies of muta tions in th ese cha nnels is not surprising,in view of their coordinated roles in the generation of actionpotentia ls. The phenotypic overlap presents a clinical chal-l en g e f o r m u t a t i on i de nt i fi c a t ion i n f a m il ie s t h a t a r e t oos m a l l for l inka ge a na l y s is . In pedi gr ees l inked t o chr omo-some 2q24, for example, i t may be necessary to screen formutations in al l of the neuronal genes in this cluster.

Evolution of Tetrodotoxin ResistanceMost voltage-gat ed sodium chan nels a re blocked by tetro-

dotoxin, a neurotoxin present in pufferfish of the fa mily Te-tra odontida e. Among th e 11 cha nnels in Table 1, the cardiacchannel SC N 5 A a n d t h e n e u r o n a l c h a n n e l s SCN10A a ndS C N 1 1 A a r e u n iq u e i n t h e ir r e si st a n c e t o t e t r od ot ox in(Gellens et al., 1992; Akopia n et al., 1996; Sangameswaran et

al ., 1996; Ta te et al., 1998). These resistant genes contain apolar amino acid, cysteine or serine, at a position in the poresegment of doma in I t ha t is occupied by a n a romatic residuein the tetrodotoxin-sensitive genes. This aromatic residue ist hought t o i nt er a c t wi t h t he hy dr ophob ic s ur fa c e of t he t e-t r o d ot o xi n m o le cu l e (F o zz a r d a n d L i p ki n d , 1 996 ). S i t e -

directed muta genesis has confi rmed th e role of th is residue int he t et r odot oxi n r esi s t a nc e of SC N 5 A (Heinemann et al .,

1992b). Tetrodotoxin resistance can be generated experimen-tally by site-directed mutation of other residues that interact

TABLE 3

Overlapping Neurological Abnormalities Associated with Mutations in Voltage-Gated I on Channels

ha n nel G en e

P henot ype

At a xia D yst onia a P a ra ly sis Migra ine S eizures

Na ϩ SCN 8A m ed jo m ed J med,med tg —

SCN2Ab

noninactivat ing transgene a

SCN1B G E F SϩC a 2ϩ CACN A1A t ot t er in g F H M tottering

E A2

SCA6CACN B 4 l et h ar gi c l et h ar gi c

CACN G2 st ar gazer st ar gazer

CACN ␣2 ␦2 K ϩ K CN A1 t ar get ed n u l l , E AM

Note. G E F Sϩ, generalized epilepsy with febrile seizures plus; EA2, episodic ataxia type 2; SCA6, spinocerebellar ataxia type 6; FHM,amilial hemiplegic migraine. Uppercase, human gene symbol; lowercase italics, mouse mutant.

a Sprunger et al. (1998).b Kearney, J . A., Plummer, N. W., Smith, M. R., Kapur, J . , Goldin, A. L. , and Meisler, M. H., manuscript in preparation.




wi t h t he t oxi n (K ont i s a nd G ol di n, 1 9 9 3 ; F ozza r d a nd Li p-ind, 1996), but mutations at these si tes have not been ob-

erved in nature.

Origin of Muscle-Specific Sodium Channels

In contrast to the sodium-dependent action potentials iner t eb r a t e m us cl e, a c t i on pot ent i a l s i n m us cl e of i nver t e-rates such as crustaceans and insects are calcium-depen-ent (Fatt and Ginsborg, 1958; Suzuki and Kano, 1977). In

most invertebrates, the expression of sodium channels ap-ears to be l imited to neurons (Tseng-Crank et al ., 1991;

Oka m ur a et al ., 1994; Dyer et al ., 1997). Sodium currentsa ve been detected in muscle of a mphioxus, an invertebra tehor da t e wi t h t he pr edupli ca t i on chor da t e genom e (Ha gi -

wa r a a nd K i dokor o, 1971; Holl a nd et al ., 1994). The datauggest that expression in muscle was a characteristic of ann cestra l chordat e sodium channel. Tha t gene ma y ha ve hadua l expression in n eurons a nd muscle. Alternat ively, mus-l e s peci fic it y m a y ha v e a r i s en i ndependent l y i n t he m a m -

malian genes on chromosome 3 and chromosome 17. Furtherna l y si s of t he s eq uence a nd expr es s ion of t he a m phi oxusenes might shed l ight on t he evolution of muscle-specifi codium channels.

Future Prospects

The evolutiona ry r ela tionships am ong the ma mma lia n so-ium channel ␣ genes in chromosomal location, exon organi-ation, and tetrodotoxin sensitivity described here provide ar a m ewor k for under s t a ndi ng t he or i gi n a nd di v er genc e ofhi s gene fa m i l y . Com pa r i s on of t he pr om ot er r egions of

members of this gene family that differ in t issue specificityould contribute to understanding the molecular evolution ofegulatory elements. Specific functional roles of the cytoplas-

m i c l oop dom a i ns i s a not her i m por t a nt a r ea for fut ur e r e-earch.

The un ique physiological role of individual sodium chan nelenes remains one of the most interesting issues in channeliology. The mammalian genome contains five neuron-spe-ific sodium channels with highly conserved amino acid se-uences and overlapping expression patterns in the central

nd peripheral nervous system (Felts et al ., 1997). Differ-nces in electrophysiologica l properties (Ram a n et al., 1997;m i t h et al., 1998), subcellular localization (Westenbroek et l . , 1989; Toledo-Aral et al., 1997), and level of expression in

specific classes of neurons (Garcia et al., 1998) cont ribute tot hei r uni q ue func t i ons . D ur i ng t he pa s t dec a de, ext ens i v e

site-directed mutagenesis produced a solid understanding ofthe sh ar ed functiona l domains involved in channel functionstha t could be a ssayed in t he oocyte system. During t he com-ing decade, analysis of neurophysiological effects of humanand mouse mutations, observed i n v i v o, wi l l s hed l i ght onuni q ue dom a i ns a nd t he evol ut ion of funct i ona l di ver si t ywithin the sodium channel gene family.

ACKNOWLEDGMENTS

P r e pa r a t i on of t h i s r e v i ew w a s s u pp or t e d b y N I H G r a n t sNS034509 an d G M24872. We th ank P riscilla Tucker for assista ncew it h int erpret a t ion of t he phylogeny. We a re gra t eful t o our col-

leagues in the Meisler laboratory and at the University of Michiganfor ma ny st imulat ing discussions. An a nonmyous reviewer providedvaluable suggestions for improving the manuscript.

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TABLE 4

The Mode of Inheritance of Sodium Channel Mutations Depends on the Alteration in Channel Function

G ene Tissue Mut a t ion E ffect on funct ion I nher it a nce P h en ot y pe

CN2A B ra in G AL879-881Q3 D ela yed ina ct iva tion,persistent current

D om in a n t F oca l m ot or a b nor m a li ti es ,generalized seizures

C N4A Muscle M1592V D ela y ed ina ct iva t ion,

persistent current

D om in a nt H YP P , episod ic m us cle

weakness, elevatedserum potassium

C N5A H ea r t ⌬K P Q 1505-1507 D e la y e d i na c t iv a t ion ,persistent current

D om in an t F at a l ca rd ia c a rr hy th mia

C N8A B r a in A1071T D epola rizin g sh ift in volt a gedependence of a ctivation

R ecessive At axia

C N8A B r a in Null C om plet e loss of a ct ivit y Recessive L et h a l pa r a lysis

Note. Representa tive examples of the known m uta tions in S CN2A (Kear ney, J . A., Plum mer, N. W., Smit h, M. R., Ka pur, J ., G oldin, A. L. ,n d Meisler, M. H., m an uscript in prepara tion), S CN4A (Ca nnon, 1997), SC N5A (B ennett et al., 1995), a nd SC N8A (Kohrma n et al., 1996;

Meisler et al., 1997).




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