受體與細胞功能調控疾病1 2

Chapter11.Receptors/signaltransductionmoleculesanddiseases1.

Hereditarydiseasesofreceptors/signaltransductionmoleculescausedbygenemutationDiseasescausedbyauto-antibodyofreceptors3.Abnormalreceptor/signaltransductionmoleculesaskeyintermediarypathogenesislinksinsomeimportantdiseases

Section1.Diseasescausedbyhereditarygeneticmutationof

receptorsandsignaltransductionmolecules(遺傳性受體和信號傳導分子的基因突變引起的疾病)TRHypothyroidism(T3,T4

)TSHRHypothyroidism(TSH

T3,T4)IRDiabetes(Insulin

)ARUnderdevelopmentofmalesexorgan(Androgen

)GHRDwarfism(Growthhormone

)ACTHRHypo-glucocorticoidsyndrome(ACTH

GC)

GRHypo-glucocorticoidsyndrome(Glucocorticoidhormone

)

IL-2RLowimmunity

(IL-2

)

More（Interleukin–2,白介素-2）CharacteristicsGenemutationofreceptor

AbnormalAAsequence

Lowaffinitytoligand

Lowresponsetointrinsicligand

Decreasedtargetcellfunction

(GenemutationofLHRmaycausehyperfunction)Diagnosis:Ligandconcinplasma(normalorhigh)

Receptorintissueorbloodcells(lowaffinity)

Geneexamination

Treatment:Replacementtherapynoteffective(exceptionspredictable)

GenetherapyTRHypothyroidism(T3,T4

)TSHRHypothyroidism(TSH

T3,T4)IRDiabetes(Insulin

)ARUnderdevelopmentofmalesexorgan(Androgen

)GHRDwarfism(Growthhormone

)ACTHRHypo-glucocorticoidsyndrome(ACTH

GC)

GRHypo-glucocorticoidsyndrome(GC

)

IL-2RLowimmunity(IL-2

)

Pseudo-hypo-parathyroidism

MutationofG-protein

PTH

PTHR

Gs

AC

cAMP

PKA

Defectsinthisdisease?BloodPTH

PTHRbindingreaction

ACresponsetoFoskolin

ActionofFluorideandGTPanalogueonAC

Gsmutation：Initialmethioninereplacedbyvaline

Simlarmutationinduceddiseaseshavebeenreportedinrecentyears:

Nightblindness(Nougaret):Gt1mutation(Gly38AsporG38D)Colorblindness(Achromatopsia):Gt2mutationWeinsteinLSetal.GeneticdiseasesassociatedwithheterotrimericGprotein.TrendsinPharmacol.Sci.2006;27(5):260-266.AbnormalexpressionofG

orG

mRNAinmultigenicdiseases:Gs:(T395C)hypertensionG3:(C825T)hypertension,metabolicsyndromes(obesity,insulinresistance),Alzhiemer’sdisease.

SiffertW.Gproteinpolymorphismsinhypertension,atherosclerosis,anddiabetes.Annu.Rev.Med.2005;56:17-28.Section2.

Diseasesduetoauto-antireceptorantibody受體自身抗體形成引起的疾病

AntibodypropertyPathologicalPolyclonalInsitubinding,eitherasagonistorasantagonistofreceptormoleculeFunctional1.Grave’sdiseasePituitaryGlandThyroidGland

Plasma

T3,T4TSH(+)Hypothalamus()()(Normal)1.Grave’sdiseasePlasmaTSI

,TSH

Specificdiagnosis：

125I-TSH+TSHR(thyroidtissue)LabelledcomplexPlasmasamplecompetition%inhibitionofLabelledcomplexservesastheindex2.MyatheniaGravis(重癥肌無力）SkeletalMuscleNervePulseAcetylcholineAnti-nAChRImmunoglobulin

(Receptorsoccupied,nostimulation,receptorsdestroyed)SerumAnti-nAChRImmunoglobulin

3.Acromegaly（肢端肥大癥）

Antibody

GHRActionofantibodysimilartoTSI,stimulateGHR4.Idiopathicmyxedema（自發(fā)性粘液性水腫）Antibody

TSHR

ActionofantibodysimilartoMyatheniaGravis,blockstheactionofTSHonTSHR5.Others受體和信號傳導分子功能異常是一些重要疾病的重要中間環(huán)節(jié)

(和治療環(huán)節(jié)）Section3.Abnormalfunctionofreceptor/signaltransductionmoleculesasimportantintermediatepathologicalprocess(andtreatmenttarget)SpilloverbindingofreceptorsRelationofsomesteroidhormonereceptortotumorAbnormalreceptor/functionasthemechanismofimportantpathologicalchangesinsomeimportantdiseases(andtherapeutictarget)1.SpillOverBindingofReceptors受體的溢出性結合

PregnantdiabetesMacrosomianewborn兒

InsulinIGF1HighaffinityHighaffinityInsulinresponseIGF1responseLowaffinity(IGF=Insulinlikegrowthfactor)

Addison’sdiseaseACTH:S-Y-S-M-E-H-F-R-W-G-K-P-V-G-K-K-R-R-P-V-K-V-Y-P-D-A-G-E-D-Q-S-A-E-A-F-P-L-E-F-MSH:

S-Y-S-M-E-H-F-R-W-G-K-P-VDarkskin

ACTH

-MSHR

pigmentinskinMelanocytestimulatinghormonereceptorGlucocorticoidhormoneACTH肢端肥大癥:

GH

乳溢，閉經

GHandPRL：45%homologyofaminosequenceBothreceptorsbelongtoFibronectin-likegroup（纖維連接蛋白）

GH

PRLR

HyperprolactinemiaSingleTMS,linkedtosolublekinase絨毛膜上皮癌

甲亢

TSHandhCGhave2subunits,samesequencefor-subunitThereforereceptorshavesimilarbindingstructureChorioepithelioma:hCG

TSHR

Hyperthyroidism兒童原發(fā)性甲減早熟TSH、FSH、LHhave2subunits,samesequencefor-subunitThereforereceptorshavesimilarbindingstructureIdiopathichypothyroidism:TSH

LH