G蛋白耦联受体

THEHUMENPERSPECTIVEDisordersAssociatedwithGprotein-CoupledReceptors文字版图文版Thehumangenomemayencodeasmanyas2000differentGPCRs.Theirimportanceinhumanbiologyisreflectedbythefactthatmorethanone-quarterofallprescriptiondrugsactasligandsthatbindtothishugesuperfamilyofreceptors.AnumberofinheriteddisordershavebeentracedtodefectsinbothGPCRsandheterotrimericGprotein.Congenitalnephrogenicdiabetesinsipidus(CNDI)isarareinheriteddiseaseinwhichinfantssufferseriousdehydrationastheresultofaninabilityoftheirkidneystoproduceaconcentratedurine.Ifnotdiagnosedpromptly,thechronicdehydrationcanproducementalretardation,inadequategrowth,andevendeath.Thedisorderresultsfromtheinabilityofthecellsofthekidneystorespondtothehormonevasopressin(antidiuretichormone).Asnotedonpage153,somecaseofthisdiseaseresultfrommutationsinaquaporins,Thewaterchannelsoftheplasmamembrane.Inmostcase,however,thefaultliesinthevasopressinreceptor,whichistypicallyshortenedastheresultofamutationthatintroducesastopcodonintothemRNA,causingprematureterminationofpolypeptidesynthesis(page484).AdifferenttypeofdebilitatingmutationinthissameGPCRleadstoanaminoacidsubstitutionatthejunctionbetweenthethirdtransmembranesegmentandthesecondintracellularloop(site4,figure1).Eventhoughthisreceptorcanstillbindvasopressinatitsexternalsurface,thereceptorcannotactivatetheGproteinandthuscannotpassthesignaldownstreamtotheeffector.人类基因组能够编码多达2000中不同的G蛋白偶联受体（GPCRs）。大约有1/4的处方药品是作为与这类受体超家族中的某一受体的配基而发挥作用的，由此可以看出G蛋白受体的重要性。相当一部分遗传性紊乱都可以上溯到GPCRs和异三聚G蛋白的缺陷。先天性肾源性尿崩症(CNDI)是一种罕见的遗传性疾病，由于患病的婴儿的肾脏缺乏产生终尿的能力，他们会遭受严重的脱水。如果没有及时地诊断治疗，这种慢性的的脱水会引发智利障碍、生长迟缓、甚至是死亡。而这种紊乱的原因是肾脏的细胞失去了对后叶升压素（抗利尿激素）的应答能力。就像153页提到的，一些病例的致病原因是水通道的突变，即质膜上的水通道的改变。然而，大多数情况是由于后叶升压素受体出现错误造成的。一种情况是编码该蛋白质的mRNA中出现了一个表示结束的密码子，导致这个多肽的编码提前结束了，因而使得编码出来的产物变短。另一种情况是一种错义突变，位于第三个跨膜片段和第二个胞内环联结处的一个氨基酸被替代了。这样，即使受体外表面能和后叶升压素结合，它也不能激活G蛋白。这样，就无法向下游的受动器传递信号了。CNDIresultfromamutationthatleadstoalossoffunctionoftheencodedreceptor.manymutationthatalterthestructureofsignalingproteinscanhaveanoppositeeffect,leadingtowhatisdescribedasa“gainoffunction.”inonesuchcase,mutationshavebeenfoundtocauseatypeofbenignthyroidtumor,calledanadenoma.UnlikenormalthyroidcellsthatsecretethyroidhormoneonlyinresponsetostimulationbythepituitaryhormoneTSH,thecellofthesethyroidadenomassecretelargequantitiesofthyroidhormonewithouthavingtobestimulatedbyTSH(thereceptorissaidtoactconstitutively).TheTSHreceptorinthesecellscontainsanaminoacidsubstitutionthataffectsthestructureofthethirdintracellularloopoftheprotein(figure1,mutationsatsites5or6).Asaresultofthemutation,theTSHreceptorconstitutivelyactivatesaGproteinonitsinnersurface,sendingacontinualsignalthroughthepathwaythatleadsnotonlytoexcessivethyroidhormonesecretionbuttotheexcessivecellproliferationthatcausesthetumor.ThisconclusionwasverifiedbyintroducingthemutantgeneintoculturedcellsthatnormallylackthisreceptoranddemonstratingthatthesynthesisofthemutantproteinanditsincorporationintotheplasmamembraneledtothecontinuousproductionofcAMPinthegeneticallyengineeredcells.CNDI是由于突变导致被编码受体的功能的缺失造成的，而很多导致信号蛋白结构改变的突变会带来相反的结果。这种现象被描述为功能的获得。比如人们发现这种突变能导致良性的甲状腺肿瘤，即腺瘤。我们下面来讨论一下为什么会出现这种情况。正常的甲状腺细胞只有在与垂体TSH（促甲状腺激素）应答时才分泌甲状腺素，而这些甲状腺瘤的细胞不用与垂体激素TSH应答就能大量分泌甲状腺素。这些细胞中的TSH受体蛋白的一个氨基酸被替代了，从而影响了蛋白质第三个胞内环的结构。这一突变使TSH受体蛋白连续不断的刺激位于它内表面的G蛋白，通过这一途径连续的释放信号，这不但会导致甲状腺素的过量分泌，同时还会导致细胞的过量增殖从而导致肿瘤。这一事实已通过实验证实。当向正常的没有这种受体蛋白的培养细胞中转入突变基因后，细胞显示出有突变蛋白产生出来，它位于脂膜的下面，并且导致了cAMP在细胞内的连续产生。Themutationthatcausesthyroidadenomasisnotfoundinthenormalportionofapatient’sthyroidbutonlyinthetumortissue,indicatingthatthemutationwasnotinheritedbutaroseinoneofthecellsofthethyroid,whichthenproliferatedtogiverisetothetumor.Amutationinacellofthebody,suchasathyroidcell,iscalledasomaticmutationtodistinguishitfromaninheritedmutationthatwouldbepresentinalloftheindividual’scells.Aswillbeevidentinthefollowingchapter,somaticmutationsareaprimarycauseofhumancancer.Atleastonecancer-causingvirushasbeenshowntoencodeaproteinthatactsasaconstitutivelyactiveGPCR.Thevirusisatypeofherpesvirusthatisresponsibleforkaposi’ssarcoma,whichcausespurplishskinlesionsandisprevalentinAIDSpatients.Thevirusgenomeencodesaconstitutivelyactivereceptorforinterleukin-8,whichstimulatessignalingpathwaysthatcontrolcellproliferation.在病人甲状腺正常的部分并没有发现引起甲状腺瘤的突变，这种突变只存在于病人的肿瘤组织中。这一现象表明，这种突变并不会遗传，它只使甲状腺组织中的某一个细胞增殖进而引起肿瘤。像这样身体内某一个细胞突变的现象就叫做somaticmutation，这样就把它与存在于全身细胞的能遗传的突变区别开来。事实上这种somaticmutation是引起人类癌症的首要原因。至少有一类能引起癌症的病毒显示出它们编码了一类具有活性的GPCR蛋白质。这是一种典型的疱疹病毒，它是导致卡波济氏肉瘤的罪魁祸首。卡波济氏肉瘤能在病人的皮肤上留下紫色的伤害，这种病在艾滋病患者群体中很普遍。病毒的基音组编码了白细胞杀菌素-8（interleukin-8）的受体蛋白，这种蛋白刺激了控制细胞增殖的信号途径。Asnotedintable1,mutationsingenesthatcodeforthesubunitsofheterotrimericGproteincanalsoleadtoinheriteddisorders.Thisisillustratedbyareportontwomalepatientssufferingfromararecombinationofendocrinedisorders:precociouspubertyandhypoparathyroidism.BothpatientswerefoundtocontainasingleaminoacidsubstitutioninoneoftheGαisoforms.ThealternationinaminoacidsequencecausedtwoeffectsonthemutantGprotein.Attemperaturesbelownormalbodytemperature,themutantGproteinremainedintheactivestate,evenintheabsenceo