Cl- channels &ligan-gatedchannelsCheng Long, chenglong_scnu@qq.comSchool of Life Sciences, South China Normal UniversityMar. 27, 20121933華南師范大学INIVERSITYSOUTH CHINANORMAL
Cheng Long, chenglong_scnu@qq.com School of Life Sciences, South China Normal University Mar. 27, 2012 Cl- channels & ligan ‐gated channels
The outline...Required Readings:JentschTJ,SteinV,WeinreichF,ZdebikAA.Molecularstructureandphysiological function of chloride channels.Physiol Rev.2002,82(2):503-568.Verkman AS, Galietta LJ.Chloridechannels as drug targets.Nat Rev DrugDiscoV.2009,8(2):153-171BenarrochEE.(2011)NMDAreceptors:recentinsightsandclinicalcorrelations.Neurology.76(20):1750-1757LuscherB,FuchsT,KilpatrickCL.(2011)GABAAreceptortrafficking-mediatedplasticityofinhibitorysynapses.Neuron.70(3):385-409.EdwardO.Mann,OlePaulsen(2oo7)RoleofGABAergicinhibitioninhippocampalnetworkoscillations.TrendsinNeurosciences.3o(7):343-349.Further Readings:DuranC,ThompsonCH,XiaoQ,HartzellHC.(2010)Chloridechannels:oftenenigmatic,rarelypredictable.AnnuRevPhysiol.72:95-121.LeeHK,KirkwoodA.(2011)AMPAreceptorregulationduringsynapticplasticity in hippocampus and neocortex.Semin Cell DevBiol.22(5):514-520
The outline. Required Readings: Jentsch TJ, Stein V, Weinreich F, Zdebik AA. Molecular structure and physiological function of chloride channels. Physiol Rev. 2002, 82(2): 503-568. Verkman AS, Galietta LJ. Chloride channels as drug targets. Nat Rev Drug Discov. 2009, 8(2): 153-171. Benarroch EE. (2011) NMDA receptors: recent insights and clinical correlations. Neurology. 76(20): 1750-1757. Luscher B, Fuchs T, Kilpatrick CL. (2011) GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron. 70(3): 385-409. Edward O. Mann, Ole Paulsen (2007) Role of GABAergic inhibition in hippocampal network oscillations. Trends in Neurosciences. 30(7): 343- 349. Further Readings: Duran C, Thompson CH, Xiao Q, Hartzell HC. (2010) Chloride channels: often enigmatic, rarely predictable. Annu Rev Physiol. 72: 95-121. Lee HK, Kirkwood A. (2011) AMPA receptor regulation during synaptic plasticity in hippocampus and neocortex. Semin Cell Dev Biol. 22(5): 514-520
The outline...This class will cover:AnionchannelsOutsidecellTypes&structureofCl-channelsFunction & classification of ClchannelsMembraneRegulation&disordersofClchannelsInsidecellNMDACarboxyterminusGABA
The outline. This class will cover: Anion channels Types & structure of Cl- channels Function & classification of Clchannels Regulation & disorders of Clchannels NMDA GABA
IntroductionAnionchannelsareproteinaceousporesinbiologicalmembranesthat allowthe passivediffusionof negativelychargedionsalongtheirelectrochemical gradient.Althoughthesechannelsmayconductotheranions(e.g,IorNO,)betterthanCl,theyareoftencalledClchannelsbecauseClis the most abundant anion in organisms and hence is thepredominant permeating species under most circumstancesClchannel gatingmaydependonthetransmembranevoltage(in voltage-gated channels),on cell swelling,on thebinding ofsignaling molecules (as in ligand-gated anion channels ofpostsynapticmembranes),onvariousions [e.g.,anions,Ht(pH)orCa2+,onthephosphorylationof intracellularresiduesbyvarious protein kinases, or on the binding orhydrolysis of ATP
Introduction Anion channels are proteinaceous pores in biological membranes that allow the passive diffusion of negatively charged ions along their electrochemical gradient. Although these channels may conduct other anions (e.g., I- or NO3- ) better than Cl-, they are often called Cl- channels because Cl- is the most abundant anion in organisms and hence is the predominant permeating species under most circumstances. Cl- channel gating may depend on the transmembrane voltage (in voltage-gated channels), on cell swelling, on the binding of signaling molecules (as in ligand-gated anion channels of postsynaptic membranes), on various ions [e.g., anions, H+ (pH), or Ca2+, on the phosphorylation of intracellular residues by various protein kinases, or on the binding or hydrolysis of ATP
Where are anion channelsencountered?Anionchannels were detected almosteverywhereInsynaptic vesiclesfrom rat brainandfromTorpedoelectricorgan,voltage-dependent anion channels of intermediateconductance(10-100pS)werefound.ThesechannelswerepresentineverysynapticvesicleReconstitutionofendoplasmicreticulummembranesfromrathepatocytesyieldedalarge-conductance(150-200pS)anionchannel,which wasalso voltage dependent.A different type ofanionchannelhasbeenfoundinsheepbrainendoplasmicreticulum membranes,where it is colocalized withcalciumreleasechannelsAnanionchannelintheGolgicomplexwascharacterizedwhichwaspresentevenintheabsenceofproteintranslationindicatingthat these channels are not en routetothe plasmamembrane,butendogenous tothis compartment
Where are anion channels encountered? Anion channels were detected almost everywhere. In synaptic vesicles from rat brain and from Torpedo electric organ, voltage-dependent anion channels of intermediate conductance (10–100 pS) were found. These channels were present in every synaptic vesicle. Reconstitution of endoplasmic reticulum membranes from rat hepatocytes yielded a large-conductance (150–200 pS) anion channel, which was also voltage dependent. A different type of anion channel has been found in sheep brain endoplasmic reticulum membranes, where it is colocalized with calcium release channels. An anion channel in the Golgi complex was characterized, which was present even in the absence of protein translation, indicating that these channels are not en route to the plasma membrane, but endogenous to this compartment
AnionexchangeproteinsSLC4A1 (AE1):Erythrocyteband3proteinMajor integral glycoprotein in erythrocyte membrane·Polymorphisms determine Diego blood groupDiseases:Spherocytosis;Ovalocytosis;Renaltubularacidosis;HypokalemicperiodicparalysisOtherSLC4A2:Anionexchanger;Choroidplexus,Gl&OtherSLC4A3:Anionexchanger;Cardiac&BrainSLC4A4:NaBicarbonatecotransporter;Renal;Renaltubularacidosis,glaucoma,cataracts,&band keratopathySLC4A5:NaBicarbonatecotransporter;PancreasSLC4A6:NaBicarbonatecotransporter;Retina
Anion exchange proteins SLC4A1 (AE1): Erythrocyte band 3 protein Major integral glycoprotein in erythrocyte membrane Polymorphisms determine Diego blood group Diseases: Spherocytosis; Ovalocytosis; Renal tubular acidosis; Hypokalemic periodic paralysis Other SLC4A2: Anion exchanger; Choroid plexus, GI & Other SLC4A3: Anion exchanger; Cardiac & Brain SLC4A4: Na Bicarbonate cotransporter; Renal; Renal tubular acidosis, glaucoma, cataracts, & band keratopathy SLC4A5: Na Bicarbonate cotransporter; Pancreas SLC4A6: Na Bicarbonate cotransporter; Retina
Anion exchange proteinsOtherSLC17A5(Sialin):Salla syndrome(Sialicacid storage)SLC26A3:Down-regulatedinadenoma(DRA)SulfatetransporterCongenitalchloridediarrheaSLC26A4:TransporterofChloride&lodideNon-syndromic deafness, congenital (DFNB4)PendredsyndromeEnlargedvestibularaqueductsyndrome
Anion exchange proteins Other SLC17A5 (Sialin): Salla syndrome (Sialic acid storage) SLC26A3: Down-regulated in adenoma (DRA) Sulfate transporter Congenital chloride diarrhea SLC26A4: Transporter of Chloride & Iodide Non-syndromic deafness, congenital (DFNB4) Pendred syndrome Enlarged vestibular aqueduct syndrome
Voltagedependentanionselectivechannelproteins(VDAC)Location:Outer mitochondrial membrane,inner mitochondrialmembrane,plasmamembraneFunctionsChannelsforsmallhydrophilicmoleculesTranslocationofadeninenucleotidesthroughoutermitochondrialmembraneBCL2proteinsbindtoVDAC:Regulatemitochondrialmembranepotential &releaseof cytochromecduringapoptosisMitochondrial binding sitefor:Hexokinase(HK1);Glycerolkinase
Voltage dependent anion selective channel proteins (VDAC) Location: Outer mitochondrial membrane, inner mitochondrial membrane, plasma membrane Functions Channels for small hydrophilic molecules Translocation of adenine nucleotides through outer mitochondrial membrane BCL2 proteins bind to VDAC: Regulate mitochondrial membrane potential & release of cytochrome c during apoptosis Mitochondrial binding site for: Hexokinase (HK1); Glycerol kinase
VDACVDAC1Pathwayformovementofadeninenucleotidesthroughoutermitochondrial membraneMitochondrial binding site forhexokinase and glycerol kinaseVDAC2Openconformation:Atloworzeromembranepotential;WeakanionselectivityClosedconformation:Atpotentialsabove 30-4o mV;Cation-selectiveVDAC3Highexpressionintestis●NullmiceSpermmotility:ReducedMuscle:Mitochondriaabnormallyshaped,Respiratorychaincomplex activityreducedVDAC4
VDAC VDAC1 Pathway for movement of adenine nucleotides through outer mitochondrial membrane Mitochondrial binding site for hexokinase and glycerol kinase VDAC2 Open conformation: At low or zero membrane potential; Weak anion selectivity Closed conformation: At potentials above 30-40 mV; Cationselective VDAC3 High expression in testis Null mice Sperm motility: Reduced Muscle: Mitochondria abnormally shaped, Respiratory chain complex activity reduced VDAC4
AniontransporterOrganicaniontransporter(OATP)Nat-independent transport of organic anions,e.g.bileacidsCanalicular multispecific organic aniontransporter(CMOAT)Dubin-JohnsonSyndromeSulfateaniontransporter
Anion transporter Organic anion transporter (OATP) Na +-independent transport of organic anions, e.g. bile acids Canalicular multispecific organic anion transporter (cMOAT) Dubin-Johnson Syndrome Sulfate anion transporter