Kidins220/ARMS as a functional mediator of multiple receptor signalling pathways

Kidins220/ARMS as a unc ional media o o mul iple ecep o signalling pa hways Ve onika E. Neub and 1, *, Fab izia Cesca 2, *, Fabio Ben ena i 2 and Giampie o Schia o 3,` 1 Ins i u o de Pa asi ologı´a y Biomedicina Lo´pez-Ney a, IPBLN-CSIC, A da. Conocimien o S/N, 18100 A milla, G anada, Spain 2 Depa men o Neu oscience and B ain Technologies, Is i u o I aliano di Tecnologia, ia Mo ego 30, 16163 Geno a, I aly 3 Molecula Neu opa hology Labo a o y Cance Resea ch UK London Resea ch Ins i u e, 44 Lincoln’s Inn Fields, London, WC2A 3LY, UK *These au ho s con ibu ed equally o his wo k ` Au ho o co espondence ([email p o ec ed]) Jou nal o Cell Science 125, 1845–1854 !2012. Published by The Company o Biologis s L d doi: 10.1242/jcs.102764 Summa y An inc easing body o e idence sugges s ha se e al memb ane ecep o s – in addi ion o ac i a ing dis inc signalling cascades – also engage in subs an ial c oss alk wi h each o he , he eby adjus ing hei signalling ou come as a unc ion o speci ic inpu in o ma ion. Howe e , li le is known abou he molecula mechanisms ha con ol hei coo dina ion and in eg a ion o downs eam signalling. A p o ein ha is likely o ha e a ole in his p ocess is kinase-D-in e ac ing subs a e o 220 kDa [Kidins220, also known as anky in epea - ich memb ane spanning (ARMS), he ea e e e ed o as Kidins220/ARMS]. Kidins220/ARMS is a conse ed memb ane p o ein ha is p e e en ially exp essed in he ne ous sys em and in e ac s wi h he mic o ubule and ac in cy oskele on. I in e ac s wi h neu o ophin, eph in, ascula endo helial g ow h ac o (VEGF) and glu ama e ecep o s, and is a common downs eam a ge o se e al ophic s imuli. Kidins220/ARMS is equi ed o neu onal di e en ia ion and su i al, and i s exp ession le els modula e synap ic plas ici y. Kidins220/ARMS knockou mice show de elopmen al de ec s mainly in he ne ous and ca dio ascula sys ems, sugges ing a c ucial ole o his p o ein in modula ing he c oss alk be ween di e en signalling pa hways. In his Commen a y, we summa ise exis ing knowledge ega ding he physiological unc ions o Kidins220/ARMS, and highligh some in e es ing di ec ions o u u e s udies on he ole o his p o ein in heal h and disease. Key wo ds: Kidins220/ARMS, Neu onal di e en ia ion, Neu o ophins, RTK signalling, Synap ic plas ici y In oduc ion The co ec de elopmen o he ne ous sys em elies on he abili y o axons and dend i es o ecognise hei a ge s. Du ing his highly egula ed p ocess, neu ons mig a e and o m unc ional connec ions in esponse o g adien s o g ow h ac o s ha egula e mul iple neu onal unc ions, including cell su i al, di e en ia ion and synap ic plas ici y (Bibel and Ba de, 2000; Chao, 2003; Huang and Reicha d , 2003). The neu o ophin (NT) amily is one o he bes -cha ac e ised g oups o neu o ophic ac o s and includes ne e g ow h ac o (NGF), b ain de i ed neu o ophic ac o (BDNF), and neu o ophin-3 (NT3) and -4 (NT4, also known as NT4/5) (Huang and Reicha d , 2001). Neu o ophins bind wi h high a ini y o h ee ela ed opomyosin ecep o kinases (T ks): NGF binds mainly o T kA, whe eas BDNF and NT4/5 bind mainly o T kB, and NT3 o T kC. In addi ion, all neu o ophins also bind o he p75 neu o ophin ecep o (p75 NTR , also known as NGFR), a membe o he umou nec osis ac o (TNF)- ecep o supe amily (Bibel and Ba de, 2000). O he g ow h ac o s ha a e pa amoun in neu onal g ow h and de elopmen a e he glial-cell-line-de i ed neu o ophic ac o (GDNF), which ac s h ough he Re y osine kinase ecep o , and he GDNF amily ecep o a(GFRa) (Pa a cha and Ledda, 2008). In addi ion, ophic ac o s such as he VEGF and he eph in–eph in- ecep o (eph in–Eph) amilies ha e c ucial oles bo h inside and ou side he ne ous sys em (Klein, 2009; Ruiz de Almodo a e al., 2009). The as majo i y o hese ligands pe o m hei physiological unc ions h ough plasma memb ane ecep o s ha ha e y osine kinase ac i i y – he ecep o y osine kinases (RTKs) – which esul s in dis inc signalling ou pu s and cellula e ec s. Howe e , how RTKs media e such di e se biological ou comes by s a ing om a common subse o signalling molecules – such as he Ras p o ein amily, he ex acellula egula ed kinases (ERKs; also known as mi ogen ac i a ed p o ein kinases, MAPKs), Ak and phospholipase Cc(PLCc)– is p esen ly unclea . The signal speci ici y o NT ecep o s is uned by a numbe o ac o s, including he epe oi e o T k ecep o s and he le el o p75 NTR exp essed by a pa icula neu on, which de e mine he subse o neu o ophins o which a pa icula neu on would espond (Cla y and Reicha d , 1994; S ohmaie e al., 1996; Hapne e al., 1998; Palko e al., 1999; S oilo e al., 2002). Upon binding o NTs, T k ecep o s dime ise and c oss-phospho yla e each o he . Ac i a ed T k ecep o s a e hen able o ec ui a numbe o adap o s h ough hei phospho yla ed esidues. A he in acellula le el, a ailabili y o di e en subs a es o adap o s could, hus, con ol signalling downs eam o T k ecep o s (Lee e al., 2001). Addi ionally, he esponse o neu o ophin signals depends on he empo al and spa ial pa e n o s imula ion. Thus, ansien o sus ained ac i a ion o he MAPK, phosphoinosi ide kinase-3 (PI3K) o Ak pa hways media es dis inc cellula e ec s, o example by p omo ing a local and as esponse a he g ow h cone compa ed wi h a slowe esponse a dis al si es, such as he Commen a y 1845 Jou nal o Cell Science soma (Ma shall, 1995; Ku u illa e al., 2000; Wa son e al., 2001). To add a u he le el o complexi y, di e en ecep o s can in e ac wi h each o he . Fo example, p75 NTR is ound in complex wi h T k, so ilin-1 (So l1) o Nogo (RTN4R) ecep o s (B on man and Fainzilbe , 2004), whe eas T kB in e ac s wi h eph in-A7 and EphA5 (Fi zge ald e al., 2008; Ma le e al., 2008). Simila ly, GDNFaR, Re y osine kinase and p o ocadhe ins coope a e o egula e neu onal su i al (Schalm e al., 2010), and he in e ac ion be ween EphB and N-me hyl-D-aspa a e (NMDA) ecep o s – an impo an class o glu ama e ecep o s – is c ucial o he modula ion o synap ic plas ici y (Dal a e al., 2000; Hende son e al., 2001). Thus, a complex in e play be ween he epe oi e o ecep o s and he a ailabili y o downs eam e ec o s ul ima ely de e mines he esponse o a neu on o a gi en s imulus. A common downs eam e ec o o hese pa hways is he sca olding p o ein Kidins220/ARMS. In mice, emb yos ha lack Kidins220/ARMS die a bi h, indica ing ha his p o ein is essen ial o li e. In addi ion o a a ie y o neu onal pheno ypes, hese emb yos show se e e de ec s in ascula de elopmen and ca diac mal o ma ions, which a e likely o be he cause o dea h (Cesca e al., 2011; Cesca e al., 2012). Mu an s o Kidins220/ ARMS ha e been desc ibed in Caeno habdi is elegans ( ag-114) and D osophila melanogas e (Dmel CG42672) (see also h p:// www.wo mbase.o g/ and h p:// lybase.o g/). Howe e , only a pa ial pheno ypic cha ac e isa ion o hese mu an s has been p o ided so a , making he analysis pe o med in mice he mos in o ma i e o da e. Kidins220/ARMS is a mul i unc ional sca olding p o ein Kidins220/ARMS was ini ially iden i ied as a subs a e o p o ein kinase D (PKD) in neu al cells (Iglesias e al., 2000), and independen ly cha ac e ised as a downs eam a ge o he signalling media ed by neu o ophins and eph ins (Kong e al., 2001). Kidins220/ARMS is an in eg al memb ane p o ein, con aining ou ansmemb ane segmen s in he cen al pa o he molecule, and N- and C- e minal ails bo h exposed o he cy oplasm (Fig. 1). Sequence analysis o Kidins220/ARMS e ealed he p esence o nume ous domains ha media e p o ein–p o ein in e ac ions. The N- e minus o Kidins220/ ARMS con ains ele en anky in epea s ( esidues 37–398 in he mouse sequence), which o m a conca e binding su ace ha is accessible o molecula pa ne s, such as he Rho–guanine nucleo ide exchange ac o (RhoGEF) T io (Neub and e al., 2010). Kidins220/ARMS has been included in he Kidins220/ ARMS and Pi A (KAP) amily o P-loop nucleo ide phospha ases (NTPases). P-loop NTPases con ain Walke A and Walke B mo i s (WA and WB, espec i ely) (Higgins e al., 1988), which a e o en in ol ed in he binding o nucleo ides and ha e been iden i ied in he jux amemb ane egions lanking he N- and C- e minus o Kidins220/ARMS. Membe s o his amily a e p edic ed o media e he assembly o p o ein complexes ha a e associa ed wi h he inne su ace o cell memb anes (A a ind e al., 2004). In e es ingly, Kidins220/ARMS binds ATP (Te esa Iglesias and G.S., unpublished), al hough a unc ional ole o i s Walke mo i s has so a no been es ablished. Thus, u he wo k is equi ed o es ablish whe he Kidins220/ARMS Anky in epea Walke A, B P oline- ich domain SAM domain KIM PDZ-binding mo i Phospho yla ion si e Caspase-3 si e Ubiqui yla ion si e T ansmemb ane egion EphA4 eph in-A1 p75NTR C kL Y1096 PKD S919 Kinesin-1 α α-syn ophin T ks NMDAR AMPAR T io SCG10 SCLIP MAP1a, 1b, 2 Neu onal su i al and/o dea h upon exci o oxici y S-SCAM T k signalling om endosomes Connec ion o ac in and MT cy oskele on Exi om TGN Localisa ion o lipid a s Sus ained MAPK ac i a ion Neu onal di e en ia ion MT cy oskele on Jak–S a signalling Synapse de elopmen VEGFRs Vascula de elopmen VEGF NT Glu K891 Key Fig. 1. Kidins220/ARMS engages in mul iple p o ein–p o ein in e ac ions. Schema ic s uc u e o Kidins220/ARMS wi h i s di e en domains and si es o pos - ansla ional modi ica ions. Also shown a e he molecula pa ne s iden i ied o da e, oge he wi h he cellula e en s ha a e igge ed by hei binding o Kidins220/ARMS (a ows). The domains o Kidins220/ARMS media ing he in e ac ion wi h he a ious pa ne s a e lis ed in Table 1. AMPAR, AMPA ecep o ; Glu , glu ama e; MT, mic o ubule; NT, neu o ophins, NMDAR, NMDA ecep o . Jou nal o Cell Science 125 (8)1846 Jou nal o Cell Science has a de ec able NTPase ac i i y, o whe he ATP binding is equi ed o i s unc ion. The C- e minus o Kidins220/ARMS includes se e al p o ein– p o ein in e ac ion domains; o example a p oline- ich egion ( esidues 1080–1092) ha binds he adap o p o ein C kL (A e alo e al., 2006), and a s e ile alpha mo i (SAM; esidues 1231–1300) (Iglesias e al., 2000; Kong e al., 2001) ha migh be in ol ed in bo h in e - and in a-molecula in e ac ions. In addi ion, he kinesin ligh chain (KLC)-in e ac ing mo i (KIM) ( esidues 1387–1426) binds he kinesin-1 mo o complex (B acale e al., 2007). The las ou amino acids o Kidins220/ ARMS cons i u e a PDZ-binding mo i ha binds he PDZ domain o a-syn ophin, he eby o ming a complex ha is associa ed wi h he EphA4 ecep o a he neu omuscula junc ion (Luo e al., 2005). The obse a ion ha Kidins220/ARMS in e ac s wi h all h ee T k ecep o s and wi h p75 NTR (A e alo e al., 2004; Chang e al., 2004) p omp ed a se ies o s udies on he ole o Kidins220/ ARMS in a ious aspec s o neu o ophin physiology, mos ly ocusing on he molecula mechanisms by which Kidins220/ ARMS media es T k signalling (A e alo e al., 2004; A e alo e al., 2006). Wi h i s mul iple domains, Kidins220/ARMS is a well-sui ed candida e o ac as a signalling pla o m, by ec ui ing cell-speci ic adap o s and e ec o s o ac i a ed T k ecep o s. Kidins220/ARMS is also in ol ed in unc ional in e ac ions wi h se e al o he ecep o s, such as glu ama e, Eph and VEGF ecep o s (VEGFRs) (Luo e al., 2005; Lopez-Menendez e al., 2009; A e alo e al., 2010; Cesca e al., 2012), hus ep esen ing an example o how di e en ophic pa hways can con e ge and, possibly, be in eg a ed a he le el o a single adap o molecule. A lis o he Kidins220/ARMS in e ac o s iden i ied o da e is p esen ed in Table 1. Kidins220/ARMS in e olu ion Bioin o ma ic analysis e ealed Kidins220/ARMS o hologues in se e al me azoans (Fig. 2A; Table 2) [(Iglesias e al., 2000; Kong e al., 2001) and (P obi Chak a a y, unpublished)]. In a phylogene ic ee, mammalian, a ian and ep ilian p o eins a e clus e ed oge he , and ha e a high deg ee o sequence simila i y (94-80% among mammals; 94-75% o e all). F og and ish p o ein sequences ha e an in e media e le el o simila i y (70-75% and 61-66%, espec i ely) compa ed wi h hose o mammalian p o eins, whe eas Kidins220/ARMS amino acid sequences in nema oda, unica a and cnida ia a e conside ably di e en om hose in he o he g oups (Fig. 2A). Ano he phylogene ic clus e o Kidins220/ARMS homologues is ep esen ed by insec s, whose p o ein sequences a e mo e simila o each o he han o any o he o ganism. Wi h he excep ion o he D. melanogas e Kidins220/ARMS sequence (which has an addi ional N- e minal ex ension) and ha o Bombus e es is ( o which an N- e minal ex ension is also p edic ed), he N- e minal egion o Kidins220/ARMS is highly conse ed, whe eas i s C- e minal pa is mo e di e gen (Fig. 2B). On he basis o his analysis, i is possible ha cy oskele al emodelling, which is he main unc ion associa ed wi h he N- e minus (Higue o e al., 2010; Neub and e al., 2010; Pa k e al., 2010), is he mos ‘ancien ’ unc ion o Kidins220/ ARMS. This ole has been main ained h ough e olu ion in o ganisms such as D. melanogas e and C. elegans, o which a canonical neu o ophin pa hway has no ye been iden i ied. As Kidins220/ARMS is p esen in cells o he immune sys em (Riol- Blanco e al., 2004; Ni e al., 2010; Jean-Mai e e al., 2011; Ni e al., 2011) and i is likely o be exp essed in he ca dio ascula sys em – hypo hesised on he basis o unc ional da a (Cesca e al., 2011; Cesca e al., 2012) – he C- and N- e minal pa s o Kidins220/ARMS migh ha e di e ged, e lec ing he di e en specialisa ion o issues and o gans in he a ious phylogene ic g oups. In e es ingly, he eph in–Eph and VEGF–VEGFR pa hways a e mo e conse ed in e olu ion han he neu o ophin- T k sys em, and ha e also been iden i ied in in e eb a es (D esche , 2002; Shibuya, 2002; Seipel e al., 2004; Mello and Bu ke, 2008). The e o e, he neu o ophic unc ion o Kidins220/ ARMS migh be a ea u e in o ganisms wi h a mo e complex ne ous sys em, whe eas in lowe o ganisms, Kidins220/ARMS migh con ibu e o he de elopmen o o he issues by modula ing eph in–Eph and VEGF–VEGFR pa hways. Kidins220/ARMS and neu o ophin signalling As p e iously men ioned, Kidins220/ARMS in e ac s wi h T k ecep o s (A e alo e al., 2004), o ming a e na y complex wi h p75 NTR (Chang e al., 2004). The in e ac ion be ween Kidins220/ ARMS and T kA is media ed by he ou h ansmemb ane Table 1. Kidins220/ARMS binding pa ne s Binding pa ne Kidins220/ARMS binding si e Re e ences AMPAR–GluA1 T ansmemb ane domains (A e alo e al., 2010) a-syn ophin PDZ-binding mo i (Luo e al., 2005) C kL P oline- ich domain (A e alo e al., 2006) EphA4 n.d. (Luo e al., 2005) Kinesin 1 KIM mo i (B acale e al., 2007) MAP1a, MAP1b, MAP2 Residues 760–1762 (Higue o e al., 2010) NMDA ecep o n.d. (Lopez-Menendez e al., 2009) p75 NTR Residues 1512–1762 (Kong e al., 2001) PDZ–GEF1 Indi ec binding h ough S-SCAM (Hisa a e al., 2007) PKD n.d. (Iglesias e al., 2000) SCG10 Anky in epea s (Higue o e al., 2010) SCLIP Anky in epea s (Higue o e al., 2010) Sep in 5 Residues 1603–1715 (Pa k e al., 2010) S-SCAM PDZ-binding mo i (Hisa a e al., 2007) T io, kali in Anky in epea s (Neub and e al., 2010) T kA, T kB, T kC T ansmemb ane domain (Kong e al., 2001; (A e alo e al., 2004) VEGFR2, VEGFR3 n.d. (Cesca e al., 2012) Kidins220/ARMS in cell signalling 1847 Jou nal o Cell Science domain o Kidins220/ARMS and he ansmemb ane domain o T kA (A e alo e al., 2004) (Fig. 1), whe eas he in e ac ion wi h p75 NTR in ol es he las 250 amino acids o Kidins220/ARMS (Kong e al., 2001) and he p75 NTR in acellula domain ( esidues 327–342) (Chang e al., 2004). The binding o T k ecep o s and p75 NTR o Kidins220/ARMS is di e en ially modula ed by neu o ophins. Fo ma ion o a Kidins220–T kA complex is NGF-dependen and pe sis s o up o 25 hou s ollowing s imula ion wi h NGF (Kong e al., 2001). The assembly o he e na y complex be ween Kidins220/ARMS, T kA and p75 NTR is howe e independen o NGF (Chang e al., 2004). In e es ingly, inc eased le els o Kidins220/ARMS educe he binding o T kA o p75 NTR , sugges ing ha Kidins220/ARMS egula es he o ma ion o ecep o complexes ha display di e en neu o ophin-binding a ini ies (Chang e al., 2004). In addi ion, Kidins220/ARMS selec i ely media es he sus ained Tunica a 0.1 Common bumblebee Bu - ailed bumble Wasp Ca pen e an Jumping an Red bee le Yellow- e e mosqui o Mala ia mosqui o F ui ly Pea aphid Body louse B.malayi Eyewo m Pig oundwo m C.elegans C.b iggsae T ichinella Sea squi Hyd a Pu e ish Zeb a ish Tilapia F og Chicken Zeb a inch Liza d Rabbi Ra Mouse Human Monkey Dog Elephan Cnida ia Nema oda A h opoda Cho da a B. e es is H. sapiens and M. musculus D. e io Ank TMWA WB P o SAM KIM D. melanogas e C. elegans PDZ-binding mo i 1250500 aa B A Fig. 2. Kidins220/ARMS in e olu ion. (A) Dend og am o Kidins220/ARMS o hologues. The b anch leng hs a e p opo ional o he amoun o in e ed e olu iona y change be ween sequences. GenBank accession numbe s a e lis ed in Table 2. (B) Schema ic o Kidins220/ARMS domain s uc u e in he indica ed species. Al e na i e splicing may occu in he C- e minal egion be ween he KIM mo i and he PDZ-binding domain (Iglesias e al., 2000). The shaded g ey box in he B. e es is sequence indica es a p edic ed N- e minal ex ension. Ank, anky in epea s; WA, Walke A mo i ; WB, Walke B mo i ; TM, ansmemb ane egions; P o, p oline- ich domain. Jou nal o Cell Science 125 (8)1848 Jou nal o Cell Science ac i a ion o MAPK signalling, wi hou a ec ing he as esponse o neu o ophins o he esponse o o he g ow h ac o s, such as epide mal g ow h ac o (EGF) (Kong e al., 2001; A e alo e al., 2004). Kidins220/ARMS is phospho yla ed on y osine esidues in esponse o NGF and BDNF, he ime cou se o which ollows he kine ics o T k au ophospho yla ion and he e o e sugges s ha his p o ein is a T k ecep o subs a e (Kong e al., 2001). In addi ion, y osine phospho yla ion o Kidins220/ARMS occu s simul aneously wi h ha o Shc and PLCc, indica ing ha his p o ein is amongs he i s o be ac i a ed in esponse o NGF (A e alo e al., 2004). The adap o p o ein C kL cons i u i ely binds he second poly-p oline s e ch o Kidins220/ARMS h ough i s SH3 domain (A e alo e al., 2006). Upon ea ing cells wi h NGF, Kidins220/ARMS is phospho yla ed a y osine 1096, causing a con o ma ional change in he C kL–Kidins220/ ARMS complex. This allows he ec ui men o downs eam modula o s o he MAPK pa hway, such as C3G and Rap1 (A e alo e al., 2006), and de e mines i s sus ained ac i a ion, which occu s mainly a la e endosomes (Hisa a e al., 2007). This e ec is highly speci ic, as pe u bing Kidins220/ARMS unc ion by using RNA in e e ence (RNAi) o dominan –nega i e Kidins220/ARMS cons uc s does no a ec he ansien MAPK ac i a ion igge ed by EGF and he ini ial s eps o MAPK signalling, which a e Ras- o Ak -dependen (A e alo e al., 2004). Impai men o BDNF-induced MAPK ac i a ion has also been demons a ed in Kidins220/ARMS-de icien neu ons (Cesca e al., 2012). Among he ansc ip ion ac o s ac i a ed by he MAPK pa hway, Kidins220/ARMS p omo es nuclea ac o - kappa B (NF-kB) signalling when cells a e ea ed wi h BDNF, media ing neu onal su i al (Snide han e al., 2008). In suppo o hese indings, Kidins220/ARMS –/– emb yos show widesp ead cell dea h in he cen al ne ous sys em (CNS) and pe iphe al ne ous sys em (PNS) and die a bi h (Cesca e al., 2011; Cesca e al., 2012). Rema kably, Kidins220/ARMS is one o he ew p o eins ha is selec i ely equi ed o he sus ained ac i a ion o MAPK signalling, whe eas mos o he o he ac o s ac in bo h ansien and sus ained signalling. Because o he ole Kidins220/ARMS has in su i al pa hways such as MAPK signalling, i is ecognised as a po en ial oncogene. Acco dingly, Kidins220/ARMS p e en s s ess- induced apop osis in melanoma cells and con ibu es o umou p og ession (Liao e al., 2007; Liao e al., 2011). In acellula a icking o Kidins220/ARMS In acellula a ic o Kidins220/ARMS is media ed h ough a di ec binding o KIM o KLC-1 and KLC-2, and is impo an in ensu ing a co ec esponse o neu o ophic s imuli in he neu onal model cell line PC12 (B acale e al., 2007). The KIM mo i o Kidins220/ARMS does no bea sequence simila i ies wi h o he KLC-binding p o eins (B acale e al., 2007; Dodding e al., 2011). Simila ly, he pa o KLC ha in e ac s wi h KIM has so a no been implica ed in ca go ecogni ion, sugges ing ha – h ough i s C- e minal egion – KLC ec ui s o he p o eins, such as 14-3-3 p o ein (Ichimu a e al., 2002) o Jun N- e minal kinase (JNK)-in e ac ing p o eins (JIPs) (Ve hey e al., 2001). Fu he mo e, o e exp ession o Kidins220/ARMS does no in e e e wi h he a icking o o he kinesin-1 ca goes (B acale e al., 2007; Hammond e al., 2008). The Kidins220/ ARMS–kinesin-1 complex migh , he e o e, cons i u e a modula sca old o he assembly o la ge p o ein complexes, in which single componen s associa e wi h KLC as well as wi h he o he domains o Kidins220/ARMS. Kidins220/ARMS migh link mo o p o eins o inac i e signalling complexes in o de o media e hei a ge ing o speci ic domains o he plasma memb ane. Once hese complexes ha e been deli e ed o hei inal des ina ion, hey would become ac i a ed upon exposu e o ophic s imuli. The a icking o Kidins220/ARMS o he plasma memb ane elies on PKD ac i i y (Sanchez-Ruiloba e al., 2006). PKD is a se ine/ h eonine kinase in ol ed in se e al cellula p ocesses, such as cell p oli e a ion and Golgi-complex a icking (Van Lin e al., 2002). Kidins220/ARMS cons i u i ely in e ac s wi h PKD and is phospho yla ed by his kinase on se ine 919 upon s imula ion wi h pho bol es e (Iglesias e al., 2000). Kidins220/ ARMS associa es wi h memb ane mic odomains a he leading edge o mo ile imma u e dend i ic cells (Riol-Blanco e al., 2004), o PC12 cells and o p ima y co ical neu ons (Cab e a- Poch e al., 2004). This lipid-mic odomain-associa ed pool o Kidins220/ARMS colocalises wi h PKD. In addi ion, Kidins220/ ARMS and PKD a e bo h p esen in he ans-Golgi ne wo k (TGN). The exp ession o a kinase-dead o m o PKD al e s he dis ibu ion o Kidins220/ARMS, causing i s accumula ion in in acellula s uc u es ha con ain TGN ma ke s. PKD ac i i y con ols Kidins220/ARMS a icking o he plasma memb ane h ough he phospho yla ion-dependen ec ui men o PDZ p o eins a he TGN (Sanchez-Ruiloba e al., 2006). The e o e, Table 2. Kidins220/ARMS o hologues and hei GenBank accession numbe s O ganism Common name GenBank accession numbe Acy hosiphon pisum Pea aphid XP_001943427 Anolis ca olinensis Liza d XP_003215436 Anopheles gambiae Mala ia mosqui o XP_320386 Asca is suum Pig oundwo m ADY40531 Bombus impa iens Common bumblebee XP_003493060 Bombus e es is Bu - ailed bumble XP_003400873 B ugia malayi Round wo m XP_001895979 Caeno habdi is b iggsae Wo m XP_002633264 Caeno habdi is elegans Wo m CAA92996 Campono us lo idanus Ca pen e an EFN63057 Canis lupus amilia is Dog XP_532865 Culex quinque ascia us Yellow- e e mosqui o XP_001843847 Danio e io Zeb a ish NP_956276 D osophila melanogas e F ui ly NP_611574 Gallus gallus Chicken XP_419939 Ha pegna hos sal a o Jumping an EFN89445 Homo sapiens Human NP_065789 Hyd a magnipapilla a Hyd a XP_002154747 Loa loa Eye wo m XP_003141375 Loxodon a a icana Elephan XP_003411847 Macaca mula a Monkey XP_001083478 Mus musculus Mouse NP_001074847 Nasonia i ipennis Wasp XP_003426415 Oikopleu a dioica Sea squi CBY24367 O eoch omis nilo icus Tilapia XP_003446685 O yc olagus cuniculus Rabbi XP_002722525 Pediculus humanus co po is Body louse XP_00242719 Ra us no egicus Ra NP_446247 Taeniopygia gu a a Zeb a inch XP_002197621 Te aodon nig o i idis Pu e ish CAG10502 T ibolium cas aneum Red bee le XP_001811729 T ichinella spi alis Po k wo m XP_003380555 Xenopus opicalis F og NP_001120159 Kidins220/ARMS in cell signalling 1849 Jou nal o Cell Science he in e ac ion wi h PKD could egula e he o ma ion o signalling pla o ms ha con ain Kidins220/ARMS and one o mo e memb ane ecep o s. Kidins220/ARMS egula es cy oskele al emodelling and neu onal di e en ia ion The unc ion o neu ons g ea ly depends on hei highly pola ised mo phology, which is es ablished du ing de elopmen (da Sil a and Do i, 2002). Neu o ophins and o he g ow h ac o s induce ea angemen s o he cy oskele on a g ow h cones and changes in gene exp ession (Hube e al., 2003), which need o be highly coo dina ed. Kidins220/ARMS is ideally sui ed o ul il his ole, because i is implica ed in neu o ophin signalling and in e ac s wi h cy oskele al componen s (Higue o e al., 2010; Neub and e al., 2010; Pa k e al., 2010). Neu i e ou g ow h equi es he o ma ion o F-ac in (Hube e al., 2003), and Kidins220/ARMS colocalises wi h F-ac in in NGF-di e en ia ed PC12 cells (Neub and e al., 2010; Pa k e al., 2010) and hippocampal neu ons (Higue o e al., 2010). In e es ingly, he amoun o F- ac in a g ow h cones co ela es wi h he amoun o Kidins220/ ARMS p esen a hese si es (Higue o e al., 2010), indica ing he impo ance o Kidins220/ARMS in cy oskele al emodelling in de eloping neu ons. Pa k and colleagues ecen ly cha ac e ised an in e ac ion be ween Kidins220/ARMS and sep in 5 (Pa k e al., 2010), a p o ein in ol ed in cy oskele al o ganisa ion and memb ane ubula ion (Tanaka-Takiguchi e al., 2009). Independen ly, we epo ed ha Kidins220/ARMS binds and ac i a es T io (Neub and e al., 2010), a RhoGEF ha p omo es neu i e ou g ow h h ough cy oskele al emodelling (Dickson, 2001; Es ach e al., 2002; Go ek e al., 2005). In NGF-s imula ed PC12 cells, his cha ac e is ic o T io has been linked o i s i s GEF domain, which ac i a es he small GTPases Rac1 and RhoG (Ba eman and Van Vac o , 2001; Es ach e al., 2002). This ac i i y o he GEF domain is egula ed by he lanking SH3 and spec in domains o T io. C ucially, Kidins220/ARMS binds o he la e egion h ough i s N- e minal anky in epea s (Neub and e al., 2010). This in e ac ion is impo an o he unc ion o T io, as o e exp ession o his domain causes widesp ead ac i a ion o Rac1. Because a localised ac i a ion o Rac1 a neu i e ips is necessa y o neu i e ex ension (Aoki e al., 2004), he o e exp ession o he anky in epea s inhibi s neu i e ou g ow h in PC12 cells and hippocampal neu ons (Neub and e al., 2010). In addi ion o he ac in cy oskele on, Kidins220/ARMS in e ac s wi h mic o ubules by binding ubulin, he mic o ubule-associa ed p o eins 1a, 1b and 2 (MAP1a, MAP1b and MAP2, espec i ely), and he s a hmin amily membe s SCG10 and SCLIP (also known as STMN2 and STMN3, espec i ely) (Higue o e al., 2010). These ac o s ha e a well- es ablished ole in neu onal mo phogenesis (Poulain and Sobel, 2009) and hei abili y o modula e mic o ubule dynamics is phospho yla ion dependen (Owen and Go don-Weeks, 2003). In his con ex , Higue o and colleagues ound a educ ion in he phospho yla ion o s a hmin and MAP1b in Kidins220/ARMS knockdown neu ons (Higue o e al., 2010). In e es ingly, down egula ion o Kidins220/ARMS in young hippocampal neu ons a ou s he o ma ion o mul iple axon-like p ocesses, whe eas i s knockdown in cells a la e s ages o di e en ia ion leads o an abe an dend i ic a bou (Higue o e al., 2010). These esul s ha e been con i med in Kidins220/ARMS 2/2 neu ons, in which longe axons and a simpli ied dend i ic ne wo k we e de ec ed when compa ed wi h wild- ype cells (Cesca e al., 2012). In summa y, Kidins220/ARMS con ols axonal and dend i ic ma u a ion by di ec ly modula ing cy oskele al dynamics and, in pa allel, by inducing changes in sus ained MAPK-dependen gene exp ession. E ec s o Kidins220/ARMS on neu onal ac i i y Neu o ophins a e equi ed o synap ogenesis and neu onal ma u a ion (Ma inez e al., 1998; Poo, 2001). In e es ingly, he exp ession le els o Kidins220/ARMS a e highly egula ed du ing hese p ocesses (Co es e al., 2007; Higue o e al., 2010). In hippocampal neu ons, Kidins220/ARMS is mo e abundan du ing ea ly s ages o di e en ia ion compa ed wi h la e s ages, when mo e synapses a e p esen and neu onal ac i i y is highe (Co es e al., 2007; Higue o e al., 2010). These indings suppo ecen esul s sugges ing ha Kidins220/ARMS exp ession nega i ely egula es he memb ane le els o he GluA1 subuni o he a-amino-3- hyd oxy-5-me hyl-4-isoxazolep opionic acid (AMPA) glu ama e ecep o (A e alo e al., 2010). Du ing neu onal de elopmen , his ecep o is a ge ed o he cell su ace o c ea e a ma u e glu ama e gic synapse (Hall and Ghosh, 2008). In he adul b ain, GluA2 is he main AMPA ecep o subuni , and he inco po a ion o he GluA1 subuni esul s in he o ma ion o Ca 2+ -pe meable AMPA ecep o s ha lack GluA2 (Bassani e al., 2009), which a e c ucial in es ablishing and main aining synap ic plas ici y (Man, 2011). Down egula ion o Kidins220/ARMS by using RNAi o in Kidins220/ARMS +/2 mice leads o an inc ease o GluA1 a he plasma memb ane, which can be also de ec ed as a ise in AMPA- ecep o -media ed cu en s (A e alo e al., 2010). In pa allel, educed le els o Kidins220/ARMS de e mine an inc ease in phospho yla ion o GluA1 a Se ine 831, which is associa ed wi h an enhanced ecep o conduc ance (Benke e al., 1998; De kach e al., 1999). In e es ingly, GluA1 bu no GluA2 co-immunop ecipi a es wi h Kidins220/ARMS (A e alo e al., 2010). These esul s sugges ha , du ing de elopmen , in egions cha ac e ised by high le els o Kidins220/ARMS, GluA1- con aining AMPA ecep o s a e e ained in acellula ly h ough an in e ac ion wi h Kidins220/ARMS. When neu ons ma u e and synapses a e o med, Kidins220/ARMS le els dec ease, allowing o he su ace exp ession o GluA1 and he es ablishmen o synap ic s eng h. The GluA1-speci ic in e ac ion o Kidins220/ ARMS he e o e sugges s ha his p o ein indi ec ly modula es Ca 2+ homeos asis a he ne e e minal, and has a ole in synap ic plas ici y. Kidins220/ARMS le els co ela e wi h he ac i i y o he neu onal ne wo k. In ma u e neu onal cul u es, Kidins220/ARMS also associa es wi h NMDA ecep o s (Lopez-Menendez e al., 2009). Upon o e s imula ion o he NMDA ecep o , o example du ing exci o oxici y o when neu ons a e depola ised, ac i i y- dependen Ca 2+ in lux h ough NMDA ecep o s leads o a dec ease in Kidins220/ARMS le els owing o ansc ip ional down egula ion (Lopez-Menendez e al., 2009) and p o ein clea age by calpain (Lopez-Menendez e al., 2009; Wu e al., 2010). Because Kidins220/ARMS knockdown causes a dec ease in he amoun o phospho yla ed MAPK (Lopez-Menendez e al., 2009), a educ ion in he exp ession o Kidins220/ARMS migh con ibu e o neu onal dea h h ough a dec ease in MAPK signalling. Acco dingly, in an animal model o ce eb al ischemia, Kidins220/ARMS le els co ela e wi h he ex en o neu onal cell Jou nal o Cell Science 125 (8)1850 Jou nal o Cell Science dea h, which was a ibu ed o exci o oxic NMDA- ecep o ac i a ion (Lopez-Menendez e al., 2009). Al oge he , hese indings indica e ha he amoun o Kidins220/ARMS is igh ly con olled and has a undamen al ole in neu onal su i al, bo h unde basal and exci o oxic condi ions. In addi ion o si es o calpain clea age (Lopez-Menendez e al., 2009; Wu e al., 2010), si es o caspase-3-dependen clea age (Ju e al., 2007) and o ubiqui yla ion (Kim e al., 2011) a e p esen in he Kidins220/ ARMS sequence. Fu he s udies a e he e o e needed o a be e unde s anding o he molecula mechanisms ha egula e he u no e o Kidins220/ARMS. Bo h exci a o y and inhibi o y ci cui s a e in luenced by Kidins220/ARMS. A dec ease o Kidins220/ARMS in hippocampal neu ons esul s in a lesse elease o c-aminobu y ic acid (GABA), whe eas o e exp ession o Kidins220/ARMS has he opposi e e ec , p obably because o a mechanism ha occu s a he p esynap ic e minal (Su achan e al., 2010). Ou ecen wo k, using cul u ed neu ons om Kidins220/ARMS 2/2 mouse emb yos, indica es ha Kidins220/ARMS egula es he eco e y o synap ic s eng h a inhibi o y GABAe gic synapses, whe eas inhibi o y basal ansmission is no a ec ed (Scholz-S a ke e al., 2012). These indings a e in line wi h p e ious da a ha show a ecip ocal ela ionship be ween neu onal ac i i y and he le el o Kidins220/ARMS (Co es e al., 2007). In e es ingly, incuba ion o hippocampal neu ons wi h ei he BDNF o he neu onal-ac i i y- modula ing e odo oxin causes an inc ease o Kidins220/ARMS exp ession, bu combina ion o hese ea men s does no ha e an addi i e e ec (Co es e al., 2007). This obse a ion sugges s ha neu o ophin- o ac i i y-dependen changes con ol Kidins220/ ARMS le els by ac ing on he same pa hway. The in ol emen o Kidins220/ARMS in neu o ophin-dependen synap ic plas ici y is u he con i med by he inding ha BDNF-induced po en ia ion o exci a o y pos synap ic cu en s is impai ed in Kidins220/ ARMS 2/2 neu ons (Cesca e al., 2012). Al oge he , hese esul s sugges ha Kidins220/ARMS unc ions as a neu onal ma u a ion and ac i i y senso . Mos o hese da a we e ini ially ob ained by acu e down- o up egula ion o Kidins220/ARMS, and ha e subsequen ly been con i med using Kidins220/ARMS +/2 mice, which exp ess 30– 40% less p o ein han wild- ype animals. In his mouse s ain, bo h basal synap ic neu o ansmission and long- e m po en ia ion (LTP) a e inc eased (Wu e al., 2009; Wu e al., 2010). In addi ion, hey show de ec s in spa ial memo y o ma ion (Du y e al., 2011), a p ocess in which a co ec balance be ween LTP and long- e m dep ession (LTD) is pa amoun (Kemp and Manahan-Vaughan, 2007; Ge e al., 2010). Because homozygous Kidins220/ARMS 2/2 emb yos die a bi h, u u e analysis o condi ional Kidins220/ARMS 2/2 mouse lines will help o u he ou unde s anding on he ole o his p o ein in synap ic plas ici y and highe b ain unc ions. Neu onal ac i i y also media es s uc u al modi ica ions ha a e impo an o de elopmen o he CNS and o synap ic plas ici y. BDNF is an impo an ac i i y-dependen ac o , which induces dend i ic g ow h and con ols dend i ic spine mo phogenesis (Cohen-Co y and F ase , 1995; McAllis e e al., 1995; Ho ch and Ka z, 2002; Liu e al., 2007). Kidins220/ ARMS 2/2 emb yos and adul Kidins220/ARMS +/2 mice display de ec s in dend i ic g ow h and b anching (Wu e al., 2009; Cesca e al., 2012), indica ing ha Kidins220/ARMS is impo an in BDNF-induced dend i ic de elopmen . Dend i ic b anching co ela es wi h he s abilisa ion o he synapse, which can be assessed by measu ing dend i ic spine u no e . Indeed, spine s abili y is educed in Kidins220/ARMS +/2 mice (Wu e al., 2009), sugges ing a ole o Kidins220/ARMS in cy oskele al emodelling e en s ha unde ly he homeos a ic con ol o hese pos synap ic s uc u es. In suppo o his idea, Kidins220/ARMS in e ac s wi h kali in (Neub and e al., 2010), a RhoGEF ha con ols he signalling e en s downs eam o EphB, NMDA and AMPA ecep o s, which modula e he o ma ion o dend i ic spines (Penzes and Jones, 2008). Kidins220/ARMS a he c oss oad o se e al signalling s eams Kidins220/ARMS is no only in ol ed in T k, NMDA and AMPA ecep o signalling, bu i is also a downs eam a ge o eph ins (Kong e al., 2001; Luo e al., 2005) and in e ac s wi h VEGFR (Cesca e al., 2012). Th ough i s in e ac ion wi h VEGFR, Kidins220/ARMS migh ha e a ole in ascula de elopmen , connec ing neu o ophins wi h VEGF signalling. Indeed, Kidins220/ARMS 2/2 emb yos e eal an abno mal ascula pa e n in he b ain (Cesca e al., 2012), simila o ha obse ed in mice lacking neu opilin-1, a co- ecep o o VEGFR (Gu e al., 2003). Addi ionally, Kidins220/ARMS is phospho yla ed when cells ha exp ess EphB2 a e s imula ed wi h eph in-B2 (Kong e al., 2001). Kidins220/ARMS also enhances EphA4 signalling, which is igge ed by eph in-A1 du ing he o ma ion o he neu omuscula junc ion h ough i s binding o a-syn ophin. Mo eo e , Kidins220/ARMS co- immunop ecipi a es wi h and is phospho yla ed by he EphA4 ecep o (Luo e al., 2005). T kB, EphA4, EphB1, EphB2, EphB3, NMDA and AMPA ecep o s a e all implica ed in synap ogenesis and dend i ic spine ma u a ion (Cons an ine-Pa on and Cline, 1998; Poo, 2001; Klein, 2009; Lai and Ip, 2009; McKinney, 2010). In e es ingly, hese ecep o s display a subs an ial c oss alk among each o he ; he NMDA ecep o is phospho yla ed upon BDNF s imula ion (Lin e al., 1998) and he EphB ex acellula domain in e ac s di ec ly wi h he NMDA ecep o (Dal a e al., 2000; Hende son e al., 2001). In addi ion, eph in-B-media ed ac i a ion o EphB leads o NMDA- ecep o -dependen Ca 2+ in lux (Takasu e al., 2002), which migh in luence he le el o Kidins220/ARMS p o ein syn hesis and i s downs eam signalling. Al oge he , hese da a sugges ha Kidins220/ARMS con ols synap ic o ma ion and s abili y by ac ing as a common downs eam a ge o T kB, NMDA, AMPA and EphB ecep o s. Fig. 3 summa ises he p esen knowledge ega ding he unc ion o Kidins220/ARMS a synapses, bo h in he p esynap ic compa men and in dend i ic spines. Fu u e s udies aimed a inc easing ou unde s anding o hese in e ac ions a e likely o e eal new aspec s o he molecula mechanisms unde lying synapse o ma ion. Fu u e pe spec i es Kidins220/ARMS o ches a es di e en unc ions in he ne ous sys em as well as in o he issues. In addi ion o he neu onal pheno ypes obse ed in he CNS and PNS, Kidins220/ARMS 2/2 emb yos show ca diac mal o ma ions and se e e de ec s in ascula de elopmen (Cesca e al., 2011; Cesca e al., 2012). Se e al epo s also indica e a ole o Kidins220/ARMS in he immune sys em (Riol-Blanco e al., 2004; Ni e al., 2010; Jean- Mai e e al., 2011; Ni e al., 2011). Wi h ull and condi ional knockou mouse lines o hand, i will now be possible o ca y ou a unc ional analysis o his e sa ile p o ein in issues o he han Kidins220/ARMS in cell signalling 1851 Jou nal o Cell Science he ne ous sys em. These ools will also allow he di e en ia ion o cell-au onomous and non-au onomous oles o Kidins220/ ARMS in i o. Fo example, ex ensi e cell dea h was epo ed in b ains o Kidins220/ARMS 2/2 emb yos, leading o abno mal en icle enla gemen (Cesca e al., 2011; Cesca e al., 2012). Abla ion o Kidins220/ARMS only in he ne ous sys em, howe e , does no yield he high le el o cell dea h obse ed in Kidins220/ARMS 2/2 emb yos (Cesca e al., 2012). Because he apop o ic egions in Kidins220/ARMS 2/2 b ains co espond o some o he a eas ha display abno mal ascula pa e ning, de ec i e ascula isa ion migh con ibu e, a leas in pa , o he ins ances o neu onal dea h obse ed in hese a eas. Like neu o ophins and hei ecep o s, Kidins220/ARMS is in ol ed in egula ing he equilib ium be ween cell dea h and cell su i al by a ec ing signalling pa hways ha ac as p incipal egula o s o his p ocess, such as he ERK pa hway (Ma in and Cla k, 2007). Indeed, T k ecep o s we e o iginally iden i ied as oncogenes (Ma in-Zanca e al., 1986). I is he e o e no su p ising ha Kidins220/ARMS was sugges ed o ha e a ole as an oncogene and ha i is o e exp essed in melanoma, a skin cance o neu al c es o igin (Liao e al., 2007; Liao e al. 2011) and possibly in o he ypes o cance . Unde s anding how o con ol he ac i i y o Kidins220/ARMS du ing umou p og ession, o example by speci ically a ge ing i s NTPase domain, ep esen s a possible a enue o he apeu ic in e en ion and an a ac i e means o s udy he balance be ween dea h and su i al signals. The in ol emen o Kidins220/ARMS in he ascula de elopmen wi hin speci ic a eas o he b ain is also e y appealing, bo h in he con ex o cance he apy and ollowing ischemic insul s, whe eby a boos in neo ascula isa ion T kB EphB NMDAR AMPAR T io o kali in Rac1 MAPK Gene exp ession T kB Modula ion o usion and ecycling o elease p obabili y o SVs Ac in Ac in Kidins220/ARMS Endosome ? P esynap ic e minal Dend i ic spine ? ? ? Synap ic esicle BDNF Exci a o y synapse Inhibi o y synapse Key Fig. 3. Role o Kidins220/ARMS a synapses. A exci a o y synapses, Kidins220/ARMS media es BDNF-induced po en ia ion, whe eas a inhibi o y synapses, i is in ol ed in neu o ophin-independen sho - e m plas ici y. In bo h cases, he obse ed cellula pheno ypes can be explained by al e a ions o synap ic esicle usion and ecycling, o changes in he elease p obabil y. The p ecise molecula mechanisms a he basis o his egula ion a e p esen ly unclea ( ed ques ion ma ks). In dend i ic spines, du ing synapse o ma ion, NMDA, T k and Eph ecep o s unde go subs an ial c oss alk wi h each o he ( ed a ows), wi h Kidins220/ARMS as a possible common downs eam a ge . Kidins220/ARMS signals o he ac in cy oskele on ia Rac1 h ough i s in e ac ion wi h T io o kali in. In pa allel, Kidins220/ARMS ac i a es neu onal su i al and di e en ia ion by he sus ained MAPK pa hway, which mainly akes place on endosomal compa men s. Kidins220/ ARMS also egula es he a ge ing o he GluA1 subuni o he AMPA ecep o o he cell su ace. Howe e , when and how Kidins220/ARMS is in e nalised is p esen ly unknown. Kidins220/ARMS migh signal o T io (o kali in) and MAPK om an AMPA- ecep o -con aining endocy ic compa men (dashed a ows), bu his hypo hesis equi es u he in es iga ion (indica ed by ed ques ion ma ks). AMPAR, AMPA ecep o ; NMDAR, NMDA ecep o . Jou nal o Cell Science 125 (8)1852 Jou nal o Cell Science migh be bene icial. Fu u e esea ch in hese a eas can e eal exci ing new di ec ions o a be e unde s anding o signal in eg a ion a cellula and issue le els, and migh o e new ansla ional oppo uni ies in impo an ields o medicine. Acknowledgemen s We hank P. Chak a a y o help wi h he bioin o ma ics analyses, and C.L. Thomas, A. Yabe, N. Schmieg and J. Scholz-S a ke o c i ical eading o he manusc ip . Funding This s udy was suppo ed by esea ch g an s om: Cance Resea ch UK ( o G.S.); he I alian Ins i u e o Technology ( o F.C. and F.B.); he I alian Minis y o Uni e si y and Resea ch [2008T4ZCNL g an numbe 2008T4ZCNL o F.B.]; he Compagnia di San Paolo, To ino ( o F.B.); Tele hon-I aly [g an numbe GGP09134 o F.B.] and he Spanish Minis y o Science and Inno a ion [g an numbe JCI-2008- 01843 o V.N.]. Re e ences Aoki, K., Nakamu a, T. and Ma suda, M. (2004). Spa io- empo al egula ion o Rac1 and Cdc42 ac i i y du ing ne e g ow h ac o -induced neu i e ou g ow h in PC12 cells. J. Biol. Chem. 279, 713-719. A a ind, L., Iye , L. M., Leipe, D. D. and Koonin, E. V. (2004). A no el amily o P- loop NTPases wi h an unusual phyle ic dis ibu ion and ansmemb ane segmen s inse ed wi hin he NTPase domain. Genome Biol. 5, R30. A e alo, J. C., Yano, H., Teng, K. K. and Chao, M. V. (2004). A unique pa hway o sus ained neu o ophin signaling h ough an anky in- ich memb ane-spanning p o ein. 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