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Home , Aquaporin 2, Bartter syndrome, Channelopathy, CLCN5, CLCN7, CLCNKA

Canal iônico;canalopatia;canalopatiaendócrina Descritores nal geneticdefects. thies with focus on recent progress regarding thepathophysiological mechanisms and functio- action potentialinendocrinecellsandoffers ashort overview ofknownendocrinechannelopa- thy, thyrotoxic hypokalemicperiodicparalysis. This reviewbrieflyrecapitulatesthemembrane mia, nephrogenic mellitus,cysticfibrosis,Dent’s , hypomagnesemia with secondaryhipocalce- syndrome, Bartter hyperinsulinemic syndrome,persistent hypoglycemia ofinfancy, neonatal orendocrine-relatedmanifestations,suchsorders aspseudohypoaldosteronism type1,Liddle and acidificationoflysosomalcompartments. dysfunctioncancauseendocrinedi- transepithelial transport, cellmotilityandgrowth,volume regulationandcellularioniccontent - pro on membranetransport citable cellsdo, relying electricalimpulsesinthesamewayotherex- cells carry found toapplyendocrine tissues.Infact,endocrine Arq Bras Metab. Endocrinol 2010;54/8 E Introduction lização doCa Nas célulasendócrinas,essescanaistêmfunçõesimportantes nasecreçãohormonal,sina- Canais iônicosauxiliamdiferentesfunçõescelulares,principalmentenatransduçãodesinal. SUMÁRIO cells, these channels play a major role in hormonal secretion, Ca Ion channels cellularfunctions,mainlyincellsignaltransduction.Inendocrine servediverse SUMMARY Ana LuizaR. Rolim genéticos recentes efisiopatologia Canalopatias emendocrinologia: achados pathophysiological insights recent geneticfindingsand Ion inendocrinology: Magnus R. DiasdaSilva das alteraçõesfuncionaisencontradas. nos recentesprogressosnoconhecimentodosmecanismosfisiopatológicos adquiridoapartir artigo propõeumabreverevisãodas canalopatiasendócrinasconhecidas,comfocoparticular secundária, diabetesinsípidonefrogênicoeparalisiaperiódica tirotóxicahipocalêmica.Este diabetes melitoneonatal,fibrosecística,doençadeDent,hipomagnesemia comhipocalcemia tipo 1, síndrome de Liddle, síndrome de Bartter, hipoglicemia hiperinsulinêmica da infância, canais iônicospodemcausardistúrbiosendocrinológicos,comopseudo-hipoaldosteronismo celular edaacidificaçãodocompartimento lisossomal(pH).Comoesperado,asalteraçõesnos Ion channel;;endocrinechannelopathy Keywords Fernando A.Soares exclusive to neuronal andmusclecells,havebeen exclusive toneuronal once thought to be properties, lectrophysiological 2+ , transporte transepitelial,regulaçãodamotilidade,volume econteúdoiônico and, the most recently genetically identified - channelopa Arq BrasEndocrinolMetab. 2010;54(8):673-81 1 , SusanC. Lindsey 2 , IzabelChiamolera Maria 1,2 Arq BrasEndocrinolMetab. 2010;54(8):673-81 1 , IldaS. Kunii 1 , RuiM. B. Maciel 1 , Aline M. Fujikawa plasma membrane alongtheconcentration gradient. the across passages thatallowspecific ionstodiffuse ion-specific are as endocrinechannelopathies. Pores to collectivelyreferred can causedysfunctionsthat are to signals. in any of these channel gatedchannelsandpumps,toreact teins, suchaspores, 2+ -mediated cell signaling, 1 ,

1,2 ,

1 Accepted onNov/29/2010 Received onNov/20/2010 [email protected] 04039-032 −SãoPaulo, SP, Brazil 11º andar Rua Pedro de Toledo, 669, Universidade Federal deSãoPaulo e Translacional, Molecular Laboratório deEndocrinologia Magnus R.DiasdaSilva Correspondence to: 2 (Unifesp/EPM), SãoPaulo, SP, Brazil Paulo, EscolaPaulista deMedicina Universidade Federal deSão deMedicina, Departamento e Translacional, Molecular Unifesp/EPM, SãoPaulo, SP, Brazil deBioquímica, Departamento e Translacional, Molecular LaboratóriodeEndocrinologia LaboratóriodeEndocrinologia review

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Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. tion ofb the excep- and adenohypophyseal cells (3). With creatic pan- stimuli withactionpotentialsincludechromaffin, to action potentials(AP).Endocrinecellsthatrespond nal cells,however, electricalimpulses,or canproduce - system(2).Bothendocrine andneuro in a“wireless” todistanttarget sites,asif anddelivered blood stream intothe secreted are out thebodybecausehormones - cleft, endocrinetransmissionoccursslowlythrough worksalong thesynaptic in whichtherapidpropagation transmission neuronal a“wired” from tion. Differently onlythousandsofasecondforthisac- ly andrequire quick- on theotherhand,transmitmessagesmuchmore cells, seconds, minutesorevenhourstoact.Neuronal system,andrequire thecirculatory through transported chemicalmessengersthatare ulation usuallyproduce byadepolarizingactionpotential. that canbedisrupted typically -70mV, inpotential inadifference resulting highlynegativethantheoutersurface, brane ismore of the mem- the inner surface membrane (1).Atrest, onbothsidesofthe the ionicconcentrationdifferences membranepotentialbyinverting theresting reestablish andgatedchannelsto pores act theionicflowfrom cascade signaling. Pumps counter cell for downstream ated by voltage-dependent ion currents (4,5). (4,5). ated byvoltage-dependentioncurrents mainlygener ADP afterameal,endocrinecellAPsare in the intracellular ratio of ATP/ to increases response voltage-gated Ca ofthefastactivation tion potentialistheresult oftheac- coupling.Theupstroke stimulus-secretion (6),whichisamechanismknownas release derived from delayed rectifying K delayedrectifying derived from those sponsible foralteringthemembrane potentialare - re ioncurrents Li andcols.(7).Themost important in1995by spontaneous oscillationswas firstproposed cells;suchmodelof such asinexcitablegonadotroph tion potentialscanalsooccur intheabsenceofagonists, Interestingly,leads to the downstroke. spontaneous ac- Ion channelopathies inendocrinology 674 whichallowstheinfluxofCa the cellsurface, modifyligand-gated channelslocatedat eral, hormones (mechanically-gated). Ingen- mechanical deformation ing (ligand-gated), voltage changes (voltage-gated) or toligandbind- thatopenorcloseinresponse proteins ofion-specifictransport agroup Gated-channels are of K (ER) Ca reticulum refilling theendoplasmic for influx iscrucial - reg orsensehormonal hormones Cells thatsecrete In general,APsbringCa + channels along the second half of phase 1 (Figure 1) 1) channelsalongthesecondhalfofphase1(Figure -cells thatdepolarizebyclosingK 2+ pool after depletion by hormone-induced poolafterdepletionbyhormone-induced 2+ channels(VDCC).Slowactivation 2+ intoendocrinecells.This + channels,L- and ATP channels in channelsin 2+ intothe - - than afastone. anactionpotentialwithalongdurationrather require emphasizingthatcellsintheendocrinesystem worth (phases1-4).Itis thewaveform throughout currents sentative endocrinecellandsummarizesthemajorion - shows aschematicdiagramoftheAPphasesrepre finitive treatment of thyrotoxicosis shouldbeaimed. ofthyrotoxicosis finitive treatment (11).Earlyandde- ion totheintracellularcompartment influxofthe of thetotalpotassiumpoolbutanincreased work whenintracellularCa of muscle excitability (Figure 2). of muscleexcitability(Figure re potassiumcur theoutward the Kirchannelreducing pathophysiological mechanism isthelossoffunction complex tothemembrane(16). We thatTPP proposed ofthe andtrafficking tetramers orheterotetramers, withtheassemblyeitherashomo- aries thatinterfere the channelandlackPDZbindingdomainbound- of locatedattheC-terminus R399X andQ407X,are (15). ThetwomostcommonKir2.6mutations(15), R205H, T354M,K366R,R399X,Q407XandI144fs in Kir2.6havebeenfoundtobeassociatedwithTPP: byT3(15).Sixmutations transcriptionally regulated inskeletalmuscleandis nel. Thischannelisexpressed KCNJ18 (17p11.1-2), paralogue, Kir2.6.Thisnovelchannel,encodedby sequencingofKir2.2and foundanew PCR anddirect KCNJ14 quence oftheKCNJ12 thecodingse- wescreened therefore regions, ulatory hormone-responsive (11-14). Kir2.xparalogueshaveconstitutivethyroid inpatientswith TPP notpresent ses (FHypokPP), are of hypokalemic paraly- in familial forms , present strated thatmutationsintheCACN1ASandSCN4A andothers havedemon- candidate genes.Ourgroup TPP isanurgent medicalcondition Thyrotoxic hypokalemicperiodicparalysis(PP) during the release ofCa during therelease T- typeCa (K ethnicity Asian populations,TPPcanoccurinindividualsofany in inadults.Althoughitismostprevalent acuteflaccid ofacquired form TPP isthemostfrequent associated with . limbs and thyrotoxicosis inthe lossofmusclestrength suddenandreversible from nt, which leads to depolarization and subsequent loss nt, whichleadstodepolarization andsubsequentloss Ca For a decade, we have been searching for TPP forTPP For adecade,wehavebeensearching ) channels(8,9).Importantly, K (11). Hypokalemiadoesnotindicateadepletion (Kir2.4) genes.We low-stringency performed 2+ channelsandcalciumactivatedpotassium - cis-elements (TREs)intheirreg is afunctionalpotassiumchan- (Kir2.2), 2+ Arq Bras Metab. Endocrinol 2010;54/8 from the ER (10). Figure 1 theER(10).Figure from 2+ content is high,especially where patients suffer where patients suffer KCNJ4 (Kir2.3) Ca channelsonly and -

Arq Bras Metab. Endocrinol 2010;54/8 VDCC voltage-dependentcalciumchannel;ERendoplasmic reticulum;I Biotechnology Information),HGMD(HumanGeneMutationDatabase)andEnsemblwebsites T channels (I 2- QuickK returns toER).3-Increase I the waveformphase1-4.1-K Figure 1.Schematicillustrationofan endocrine cell action potential. The majorelectrophysiologicalfeaturesofioncurrents(I) areillustratedthroughout able 1.Ionchanneldefectsassociatedwithendocrinedisorders.DatafromOMIM(OnlineMendelianInheritanceinMan),NCBI(NationalCenterfor Channel hClC-Kb TRPM6 ENaCα CLCN7 ENaCb ENaCγ CLC-5 Kir6.2 Kir2.6 Kir1.1 AQP2 AQP2 SUR1 CFTR K ), whichcanbedividedintoultrarapid(I + goesout(Ito)andrelativelymoreK SCNN1G SCNN1B SCNN1A CLCNKB KCNJ11 KCNJ18 TRPM6 ABCC8 CLCN5 CLCN7 KCNJ1 AQP2 CFTR

Membrane potential (mV) +40 -80 -60 -40 Xp11.23-p11.22 16p12.2-p12.1 0 Kir 12q12-q13 17p11.1-2 outandCl 11p15.1 11p15.1 1p36.13 9q21.13 + 7q31.2 12p13 16p13 16p12 11q24 channelclosed(K 1. Depolarizationphase 4. Restingpotential Kur - influx. 4-ExcessK ), rapid(I NW_003315950 + NM_000492 NM_000352 NM_000525 NM_000085 NM_001038 NM_000336 NM_001287 NM_000084 NM_001039 NM_017662 NM_000220 NM_000486 leavescell(I RefSeq ID Kr 0 ) andslow(I ATP (NCBI) in b TO -cell); IncreaseI transientoutwardcurrentofvoltage-gatedK 1 + Ks outsidediffusesaway; increaseNa ) components;SERCAisaERCa Kr , I T ime (ms) Ks 3. Afterhyperpolarization 2. Repolarizationphase Persistant hyperinsulinemic Persistant hyperinsulinemic , I Neonatal diabetesmellitus Neonatal diabetesmellitus Pseudohypoaldosteronism Pseudohypoaldosteronism secondary secondary Bartter syndrometypeIII hypoglycemia ofinfancy hypoglycemia ofinfancy Bartter syndrometypeII Thyrotoxic hypokalemic Hypomagnesemia with Kur Nephrogenic diabetes Pseudoaldosteronism Pseudoaldosteronism 2 (Liddle syndrome) (Liddle syndrome) ); Ca Threshold ofexcitation Dent’s disease Disorder Ca2+ insipidus 2+ type 1 type 1 type 1 -activated K (VDCC) fromoutsidemembrane;then moreCa 3 2+ 4 pumpSarco(Endo)plasmicReticulumCa + channelopens;lessCa + channel;I mutations + (HGMD) 4. 3. 2. 1. action potential Major eventsinendocrinecell /K 1489 N. of 243 134 + 82 37 23 51 46 57 37 35 15 Excess potassiumoutsidediffuses Increase potassiumout;chlorideinflux Calcium currentshutsoff; Potassium currentshutsoff;calcium away; increaseNa out; SERCApumpreturnsCa influx (fromoutside,laterfromER) 6 -ATPase pump. Kr , I Ks , I Kur aremajorrepolarisingcurrentsofoutwardlyrectifying K Altered epithelialtransport Impaired boneresorption Renal saltlossincreased Renal saltlossincreased concentration ofcalcium Renal magnesiumloss Insulin hypersecretion Insulin hypersecretion Insulin hyposecretion Renal sodiumuptake Renal sodiumuptake Impaired Hypokalemia dueto T3-excess inducing Functional defect 2+ increased K Renal waterloss Decrease serum Ion channelopathies inendocrinology in,increaseSERCApumpactivity(Ca Renal saltloss Renal saltloss Renal saltloss + /K acidification + -A 2+ TPase pump -ATPase. + shift 2+ 2+ toER fromERruntocytoplasm. Schlingmann and Kornak andcols., Walder andcols., Chang andcols., First published Simon andcols., Simon andcols., Fisher andcols., van Lieburgand cols., 1995(28) cols., 1996(29) cols., 1989(35) cols., 1994(14) cols., 1995(15) cols., 1994(53) cols., 2002(20) Ryan andcols., Shimkets and Hansson and Thomas and Thomas and Riordan and reference 1997 (24) 1996 (13) 1996 (23) 2001 (46) 1995 (42) 2002 (19) 2010 (8) 675 2+ +

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. glands, respiratory tract,colonicmucosaandkidneys. glands, respiratory seen inmanytissues,including sweatglands,salivary is resistance of manyepithelialtissues,and ofthisdisease. form severe nelopathy andisthemore isanionchan- channel(ENaC).TheARform 676 tivating mutationsinα is caused by inac- of PHA type 1 (19), while the AR form causetheautosomaldominantform corticoid sive (AR) trait. Inactivating mutations in themineralo- - dominant (AD)traitorasageneralizedautosomalreces of PHAtype1canbeinheritedeitherasanautosomal form physiologic andgeneticcharacteristics:therenal therapy(18). tomineralocorticoid fail torespond however, PHAissuspectedwhen patients normal. are functions, renal andadrenal filtration, Glomerular tomineralocorticoids. due toaperipheralresistance elevated grossly concentrationsare nin andaldosterone - tothriveintheneonatalperiod(17). Plasmare failure hypokalemia,metabolic acidosisand hyponatremia, Symptomsinclude , sponse to aldosterone. - re described in1958.Itisassociatedwithadecreased that was first salt-wasting disorder PHA type 1 is a rare Pseudohypoaldosteronism (PHA)type1 receptor;SR:sarcoplasmicreticulum. receptor; RyR:ryanodine to depolarizationandlossofmuscleexcitability. DHP:dihydropyridine of functiontheKirchanneldecreasesoutwardpotassiumcurrentleading Figure 2. Excitation-contraction coupling of . In TPP, loss Ion channelopathies inendocrinology ENaC is expressed intheapicalplasmamembrane ENaC isexpressed This disease has two distinct forms with different withdifferent This diseasehastwodistinctforms (v DHP receptor Ca2 oltage sensor) T- Kir channel tubule + Mutated Myofilaments Ca 2+ , K β RyR + andγ 3Na Ca 2+ Na/K-A Pump + SR Ca subunits of the epithelial subunitsoftheepithelial 2+ Ca TPase SERCA2 2+ Ca 2+ Cl Cl - - Extra cellular Intra cellular thus, requires lifelong therapy and treatment. lifelongtherapyandtreatment. thus, requires withageand, dition doesnotspontaneouslyimprove theARcon- UnliketheADform, functioning proteins. frameshiftornonsense,leadingtonon- these genesare mutationsin SCNN1G (18,20-22).Mostreported SCNN1A, ENaC subunitgenesare , are ineffective. are spironolactone, antagonists,suchas receptor that mineralocorticoid topointout (23).Itisimportant lial sodiumtransport inhibitepithe- thatdirectly andtriamterene, suchas involves alow-saltdietandtheuseofdrugs, ing channels by slowing degradation (25). Treatment most importantly, thenumberoffunction- increasing ofopeningand, theprobability activity byincreasing twomechanisms:enhancement ofthechannel through (24). ThesemutationsleadtoENaCgain-of-function subunits oftheepithelialsodiumchannel(ENaC) oftheβ(SCNN1B)andγSCNN1G boxyl terminus or . andpotassiumwasting inthedistal sodium reabsorption to an of theepithelialsodiumchannel(ENaC),whichleads low.are Thisdiseaseiscausedbyactivatingmutations levels activityandaldosterone adulthood. Plasmarenin be asymptomaticandmaynotdetecteduntilearly beginsinchildhoodbutcan frequently Hypertension hypokalemiaandmetabolicalkalosis(23). pertension, withhy- patientspresent (23).Affected pertension ofendocrinehy- inherited autosomaldominantform wasfirstdescribedin1963.Itisan Liddle syndrome Liddle syndrome cation channel, subfamilyM,member6(TRPM6) (26, potential caused bymutationsinthe transient receptor (27). asaconsequence of failure toparathyroid is secondary damageanddeath.Hypocalcemia sult inneurological - canre thedisorder cramps (26,27).Ifleftuntreated, andmuscle hypocalcemia,leadingtoseizures ondary hypomagnesemia and sec- individuals showsevere Affected afterbirth. shortly abnormalities in diseasethatresults cemia isanautosomalrecessive hypocal- Familial hypomagnesemiawithsecondary hypocalcemia Hypomagnesemia withsecondary genes, which truncate thecytoplasmic car SCNN1G genes,whichtruncate Liddle syndrome iscausedbymutationsin SCNN1B Liddle syndrome Hypomagnesemia with secondary hypocalcemiais Hypomagnesemia withsecondary endocrine hypertensive disorder due to increased duetoincreased disorder endocrine hypertensive Arq Bras Metab. Endocrinol 2010;54/8 SCNN1B and - Arq Bras Metab. Endocrinol 2010;54/8 (e.g.,PGE show elevatedlevelsofprostaglandins syndrome Urine samplesinpatientswithBartter genemutations. autosomalrecessive predominantly with correlated thatare syndrome types ofBartter limb (TAL) fivedifferent are There ofthenephron. inthethickascending transporters tubular electrolyte iscausedbydysfunctionalrenal hood. Thisdisorder orpolyuriaanddehydrationinearlychild- withpolyhydramniosduringpatients oftenpresent levels(28,29).Affected andaldosterone evated andel- tolowblood pressure bolic ,normal nal tubulopathycharacterizedbyhypokalemicmeta- - (BS)isaninheritedsalt-losingre syndrome Bartter sium supplementation. ofmagnesium(26). excretion absorption andrenal intestinal patientshaveabnormal ion channel.Affected kinaseandacalciummagnesium both aprotein the . thatfunctionsas Itencodesforaprotein 27). ) gene mutations (28,29,31). by ClC-Kb( CLCNKB) genemutations (28,29,31). iscaused syndrome, type III,alsocalledclassicBartter’s chloridechannelsandcauseBStypeIV.tin, affect BS - tion. MutationsinBSDN,thegenethatencodesBart membrane localiza- subunitforproper tioning Barttin afunc - basolateral side.Thesechloride channelsrequire cal renal outer medullary K outermedullary cal renal member 1 potassiumchannel,subfamilyJ, the inwardly-rectifying mutationin from defects.BStypeIIresults transport inactivetranstubular salt SCL12A1 mutationsresult 3). with onepotassiumandtwochlorideions(Figure TAL sodiumtogether luminalmembraneandreabsorbs (NKCC2).NKCC2arisesonthe ride cotransporter sodium potassium chlo- the apicalfurosemide-sensitive of thefiveBStypes(29). BStypeIIIistypicallythemildestand . Patients withBStypeIorIIhavehypermagnesiuria type IV patients experience sensorineural deafness. dysfunction, BShyposthenuria. Inadditiontorenal Patients withBStypesI,IIorIVhaveisosthenuria Cl NaK-ATPasedium exits through and chloride exits via paracellular absorptionofcalciumandmagnesium.So- for thedrivingforce the luminalspace.Italsoprovides ofpotassiuminto foradequate recirculation is required - channel K Patients require life-long treatment withmagne- life-longtreatment Patients require encodes gene,SCL12A1,encodes In BStypeI,theaffected TRPM6 is expressed intheintestinalmucosaand TRPM6 isexpressed ( KCNJ1) gene(30).encodestheapi- + proteins (ClC-Ka and ClC-Kb) on the (ClC-Ka and ClC-Kb) on the proteins + (ROMK1) channel, which (ROMK1)channel,which 2 ). ).

ROMK1: renal outer medullary K ROMK1: renaloutermedullary rectifier potassiumchannel subunits(Kir6.2).TheK rectifier inward 1(SUR1)andfourpore-forming receptors urea cemic hypercalciuria and low PTH levels. andlowPTHlevels. cemic hypercalciuria CASR inhibitsROMK1activity, whichleadstohypocal- inothertissues,suchasthekidney.pressed Activationof (PTH)butisalsoex- hormone ofparathyroid cretion se- (CASR) gene(32).CASRisessentialforregulating the extracellularbasolateralcalciumsensingreceptor iscausedbyagain-of-function mutationin syndrome, BS typeV, ofBartter anautosomal dominantform cotransporter; ClCKA: channelK (adapted fromreference29).NKCC2:sodiumpotassiumchloride Figure 3.Iontransepithelialtransportinthickascendinglimbcells K ABCC8 andKCNJ11genes(34,35).Thepancreatic mutationsthatinactivate inherited autosomalrecessive infants(4). to glucagonadministrationinaffected alsoknowntoriseinresponse levels. Glucoselevelsare high insulin levels and raised C-peptide inappropriately fattyacidlevels, ketotic hypoglycemiawithlowserum lepsy (33). Diagnosis is based on thedetection of non- properly, andepi- mentalretardation cancausesevere andtreated andcomathat,ifnotrecognized symptomsincluding severe mayshowmore newborns feeding andirritability, Some afterbirth. ariseshortly clinical signs,includinghypoglycemia,lethargy, poor hypoglycemia inneonatesandinfants(33).Typical most common cause of nontransient hyperinsulinemic (HHI), also named congenital hyperinsulinism, is the Persistent hyperinsulinemichypoglycemiaofinfancy (HHI) Persistent hyperinsulinemichypoglycemiaofinfancy ATP The most common causes of persistent HHI are The mostcommoncausesofpersistentHHIare 2CI Na K channelisafunctionalcomplex offoursulfonyl- Lumen + Mg Ca ROMK1 + - NKCC2 2+ 2+ K + + + . proteinA;ClCKB:channelK Ion channelopathies inendocrinology CI CI - - Barttin Barttin 3Na Pump + Blood 2K NaK-A CLCNKB + CLCNKA TPase + proteinB; 677 ATP

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. unit oftheK genes. ActivatingKCNJ11genemutations(Kir6.2sub- 678 Clinicalmanifestations about 1in2,500 livebirths. of inCaucasians,withafrequency disorder recessive (CF)isthemostcommonautosomal Cystic fibrosis Cystic fibrosis NDM(PNDM). and permanent transientNDM(TNDM) hastwoforms: disorder rare with ketoacidosis (36). This glycemic and some present markedly hyper able C-peptidelevels.Mostpatientsare adiposetissueandlow orundetect- weight, decreased tothrive,lowbirth failure slowed intrauterinegrowth, as neonataldiabetes(NDM).NDMisassociatedwith Hyperglycemia during the first six monthsof life is defined Neonatal diabetesmellitus account forabout10%-15%ofpatients(5). 60% ofpersistentHHIcases,whileKCNJ11 associatedwith50– for SUR1.ABCC8mutationsare tion. - ofbeta-cellinsulinsecre channel isacriticalregulator Ion channelopathies inendocrinology Activating mutationsinK (5,36,37). leads tocalciuminfluxandinsulinsecretion andmembranedepolarization.This,inturn, nel closure with NDactivatingK commonly causedbygeneticvariationsinK 6(6q24),whilePNDM ismost ties onchromosome months(37). usuallywithinthree TNDM resolves 50%-60%ofcases, Inapproximately time ofpresentation. at the is no clinical distinction between these two forms intracellular ATP inK whichresults production, primarilyassociatedwithTNDM. subunit) are neonatal diabetes).MutationsinABCC8gene(SUR (developmentaldelay,DEND syndrome epilepsyand associatedwithTNDMoramultisystem disease, are of PNDM(37).Lesscommonly, KCNJ11mutations turnover, regulation and open-state frequency (4,5). (4,5). turnover, andopen-statefrequency regulation the K canbindtotheSUR1subunitandclosing Sulfonylureas insulinsecretion. ofglucoseandreduce in thepresence ity toATP open inhibition,whichcausesthemtoremain mutations cause multiple abnormalities in K mutations cause multiple abnormalities low plasmaglucoselevels.Atthemolecularlevel,these despite membrane depolarizationandinsulinsecretion, Inactivating mutations result inpersistentb Inactivating mutationsresult Most TNDM In healthy individuals, the presence of glucose leads to ofglucose leadsto In healthyindividuals,thepresence KCNJ11 encodesforKir6.2andABCC8 ATP channel and, thus, can be used to treat patients patients channeland,thus,canbeusedtotreat ATP channel)accountfor31%-64%ofcases - duetoabnormali cases (70%)are ATP channel mutations (5). channelmutations(5). ATP channels decrease sensitiv- channelsdecrease Unfortunately ATP ATP mutations ATP channels channels channel encodes , there , there chan- -cell -cell - suggest that there are nutritional benefits(43). are suggest thatthere isevidence to outcomes, but there long-term improves in somecountries.Itisunclearwhetherearlydiagnosis individuals withpositivesweattest. mended (38); however, some suggest DNA testing in - CFTRgenotypingisrecom marginal sweattestresults, analysisisdiagnostic. In casesof mmol/L on repeated related common CFTRmutation in patients with cystic fibrosis- insufficiency.4 or5donothavepancreatic Themost insufficiency,with pancreatic patientswithclass whereas associated themostcommonand are 1-3 mutationsare Class functioningCFTR . duction ofreduced - andclassVindicatingpro production defective protein a gradientofCFTRdysfunction,withclassIindicating represent classesthat dividedintofivedifferent tions are tions havebeendescribedthusfar(42).Thesemuta- binding lectin2genes(41).Over1,800CFTRmuta- factorbeta-1andmannose- growth such astransforming of gene modifiers, the typeofmutationandpresence to branes (40).Thediseasephenotypevariesaccording adefectivechloridechannelin epithelialmem- produces gene (CFTR)that membrane conductanceregulator diabetesmellitus(39). etiology ofcysticfibrosis-related inthe ever, ofinsulinresistance totherole withregard conflictingdata,how- are use.There systemic steroid infectionandinflammation tors, includingchronic diminished inpatientswithCFduetoanumberoffac- withage.Insulinsensitivityis increases its prevalence inthefirstdecadeoflifeand Diabetes mellitusisrare indiabetesmellitus. may leadtob-celldeathandresult poorlyunderstood thatare processes other concurrent (38).Thisand andfibrosis intissuedestruction results which activation of digestive proenzymes, premature and concentrations ofHCO3,whichcauseretention withlow secretion volumeofpancreatic reduced from in85%-90%ofcasesandisthoughttoresult present ity andmortality. is insufficiency Exocrinepancreatic losis) (38).Lungdiseaseisthemaincauseofmorbid- (saltwastingwithmetabolicalka- syndrome Bartter’s andpseudo- elevated chloridelevelsinsweat,infertility insufficiency, infection,pancreatic include pulmonary bular syndrome characterized bylow-molecular-weightbular syndrome tu- renal proximal Dent’s diseaseisaX-linked recessive Dent’s disease Neonatal screening for cystic fibrosis is carried out iscarried forcysticfibrosis Neonatal screening than60 A concentrationinsweatchloridegreater trans- CF iscausedbyamutationinthecysticfibrosis is Phe508del (39). diabetes mellitusisPhe508del(39). Arq Bras Metab. Endocrinol 2010;54/8 Arq Bras Metab. Endocrinol 2010;54/8 in thesubunitsofvascular-type H due to mutations (CLCN7), while60%ofthe cases are have geneticdefectsontheosteoclastchloridechannel spaces(49).About15%ofthesepatients the marrow causesnearobliterationof cified metaphysealcartilage boneandcal- toresorb inwhichfailure sive disorder (49,50). teopetrosis) typeIV(infantileos- osteopetrosis autosomal recessive typeII(Albers-Schönberg disease)and osteopetrosis (CLCN7)cancauseautosomal dominant nel-7 protein Mutations inthegenethatencodeschloridechan- Osteopetrosis isinvolved. geneticheterogeneity gests further found,whichsug - CLCN5 andOCRL1mutationswere withsymptomsofDent’s disease,no patients presenting ofLowe(48).In some syndrome the oculocerebrorenal mutations intheOCRL1gene,thatisalsomutated ofcases,thediseaseisassociatedwith (47). In15percent seenwithDent’sdisease forproteinuria responsible are impair acidification of vesicles in the endocytotic pathway . Thus,lossoffunctionCLC-5mutationsthat takenupby proteins toprocess Acidification isnecessary it facilitates acidification (47). cells where bular proximal with proton-ATPase insubapicalendosomesofthetu- CLC-5 isfoundprimarilyinthekidneysandexpressed antiporter, CLC-5 (46). encodes the chloride-proton mutations inthechloridechannelgene,CLCN5, factors(45). modifying genesorenvironmental tion. Itisunknownwhetherthisvariabilitydueto familieswiththesamemuta- well asbetweendifferent membersofthesamefamilyas varies betweenaffected hood (44,45).Interestingly, ofrickets theoccurrence bonedisease in child- or , with deforming males also have 25% of affected Approximately (44). failure renal bolic bonediseaseandprogressive meta- , hypercalciuria, , transplantation in children with severe disease(53). withsevere transplantation inchildren tohematopoieticstemcell therapy asanalternative opens upthepossibilityforgenereplacement petrosis involvemement(52). andcranialnerve deformities skeletal , manifestations includefractures, endplatesandpelvicbone.Clinical ing ofthevertebral withthicken- acterized by generalized (51). - autosomalreces isarare Infantile osteopetrosis causedby ofDent’sdiseasecasesare Sixty percent The characterizationofgeneticdefectsinosteo - typeIIischar Autosomal dominantosteopetrosis + -adenosine tri- that that - K membrane potential towards theK membrane potentialtowards lated K K potentialandisblockedbyTRH.Inthesecells, resting K rect AQP2 to the cell surface (58). AQP2tothecellsurface rect suchasmolecules tohelpdi- therapeutic approaches, forthedevelopmentof sponsible forNDIisimportant along theconcentrationgradient. collecting ductandallowingwatertobereabsorbed ofthe thewaterpermeability nal membrane,increasing tothelumi- of ADH,thevesicleswithAQP2traffic isknowntooccur(57).Under theinfluence reuptake water regulated tubuleswhere collecting ductsofrenal (55). havebeenreported heritance patterns With families,othergenesmaybeinvolved. in someaffected notfound mutations intheabovementionedgeneswere in theaquaporin-2(AQP2)gene(56).However, since (V2)geneand receptor by mutationsinthevasopressin childhood (55).Inthemajorityofcases,NDIiscaused orinearly and isusuallydiagnosedsoonafterbirth NDI is rare calcemia and hypokalemia (54). Hereditary especiallylithiumtoxicity,drugs, disease,hyper renal causesinclude imbalance.Acquired tion andelectrolyte waterloss,patientsmayexperiencedehydra- increased tocompensateforthe If fluidintakeisnotsufficient theabilityofkidneytoconcentrateurine. decreasing (ADH), hormone isinsensitivetoantidiuretic nephron genic In nephro Nephrogenic diabetesinsipidus Ca inintracellular potential firing leading toan increase intherateofaction can beaccompaniedbyanincrease membrane depolarization.Membrane depolarization through secretion mone (TRH) stimulates prolactin by changesintheirexcitability. hor releasing Thyroid isregulated lactotrophs anteriorpituitary tion from - secre cells, hormone As with other neuroendocrine steroidogenesis induced prolactsecretioaov Perspectives: channelsontrollingTRH- reduction oftheK reduction (59). TRH-induced currents tial with small outward + + + channels that mediate Kir currents byshifting the channelsthatmediateKir currents byether-à-go-go istypicallycarried - (erg) re current contributes to the maintenance of the (Kir) current 2+ - Elucidation ofthemutationsandmechanismsre primarilyinprincipal cellsofthe AQP2 isexpressed content. In lactotroph cells, an inwardly rectifying rectifying cells,aninwardly content.Inlactotroph mutations, both recessive anddominantin- AQP2 mutations,bothrecessive + channels. Erg channels are voltage-dependent channels.Erg channelsare (NDI), the distal diabetes insipidus(NDI),thedistal + - is mediatedbyaGpro erg current Ion channelopathies inendocrinology + equilibriumpoten- ary 679 - -

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. study (10).TheauthorsshowedthattheactivityofCa limit TRH-inducedpathologicalhyperprolactinemia. cal neuroendocrine system in control ofsteroidogenesis. systemincontrol cal neuroendocrine andthe lo- is an interaction between systemichormones cin andacetylcholine.Thesefindingssuggestthatthere invitrobyoxyto- regulated traovarian signalingandare 680 was reported. relevant tothisarticle nopotential conflictofinterest Disclosure: Foundation(FAPESP). Paulo StateResearch by São is supported Theauthors’ research support. for secretarial fordailytechnicalassistanceandAngela Faria Furuzawa Gilberto tins forhelpfuldiscussions.We alsothankTeresa Kasamatsuand Mar Reinaldo Furlanetto,LuizaMatsumuraandJoãoRoberto theirpatients,andtoprofessors forreferring Maurício Carvalho MariaCristinaCosta,Conceição Mamoneand de Pereira, GláuciaMazeto,HansGraf,LiaFiorin, MariaAdelai- Carvalho, Jurado, CéliaTengan, Cláudio Kater, GabrielaSaraiva,Gisah Acknowledgment: We gratefultoDrs. Alain Gabbai,Cássia are endocrinediseases. to treat ofnewtherapeuticstrategies opment andformulation of excitable endocrine cells that can lead to the devel- knowledge willhelpusunderstandtheuniquebiology tuningspecializedcellularfunctions.This hormonally and diating theendocrinesystembyfiring,controlling inme- role summary, ionchannels playanimportant poses involved,primarily, In withmetabolicregulation. physiologicalpur anumberofdifferent tional, serving multifunc- that someionchannelsinendocrinecellsare endocrinechannelopathies. Itislikely agnoses ofrare tohelpphysiciansmakemoleculardi- channel disorders have focusedonthemolecularbiologyofendocrineion includingours, groups, pophyseal cells).Afewresearch - (neurohy cells)and osmoregulation and gonadotroph junction),chemotransduction (ovarian (neuromuscular excesstoxicity hormonal acidification (chondrocytes), (b-cells),mechanotransductionand secretion hormone manyoftheseionchannelsplayin therole from part, stems,in nel diversityinendocrinecells.Thisinterest inunderstandingionchan- interest isgrowing There conclusion to target theerg K this pathwaymayallowthedevelopmentofnewdrugs tein-coupled intracellular signal cascade. Elucidationof Ion channelopathies inendocrinology sation ofCa losa cellsoftheovary, intheces- role playsaprominent the plasma membrane.TheseBK activated K Another promising field has emerged from Kunz’s Kunz’s fieldhasemerged from Another promising + channel(BK 2+ -induced cellular responses by repolarizing byrepolarizing -induced cellularresponses + current (60)and,consequently, current Ca ), present inluteinizedgranu- ), present Ca channels mediate in- 2+ - - - 20. 19. 18. 7. 1 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. References

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