來(lái)自約翰霍普金斯醫(yī)學(xué)院,，霍德華休斯醫(yī)學(xué)院遺傳醫(yī)學(xué)研究院,，神經(jīng)科學(xué)系,，南伊利諾斯大學(xué)醫(yī)學(xué)院,，紐卡斯?fàn)柎髮W(xué)（The University of New Castle）,，北京大學(xué)第一附屬醫(yī)院等處的研究人員通過(guò)遺傳學(xué)和功能學(xué)研究證明了帶有可變動(dòng)力學(xué)特征的突變iGluR3與人類(lèi)中度認(rèn)知損傷（moderate cognitive impairment）有關(guān),。這為了解代謝型谷氨酸受體AMPA受體的作用機(jī)理，以及深入研究學(xué)習(xí)和記憶的細(xì)胞模式提供了重要資料,。這一研究成果公布在《美國(guó)國(guó)家科學(xué)院院刊》（PNAS）上,。
文章的通訊作者是來(lái)自約翰霍普金斯醫(yī)學(xué)院的王濤（Tao Wang，音譯）副教授,，第一作者是同屬約翰霍普金斯和北京大學(xué)附屬第一醫(yī)院的吳葉（Ye Wu,，音譯）博士。
在大腦中難以計(jì)數(shù)的突觸中,，目前認(rèn)為興奮性突觸執(zhí)行著學(xué)習(xí)和認(rèn)知的主要功能,。谷氨酸是大腦中含量最多，功能最強(qiáng)的興奮性突觸遞質(zhì),。谷氨酸在突觸后膜上的受體被受體特異性的激動(dòng)劑分為幾類(lèi),，NMDA受體，AMPA受體和代謝型谷氨酸受體是最主要的三類(lèi),。其中α-氨基-3-羥基-4異惡唑-丙酸（α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid,，AMPA）受體與突觸可塑性密切相關(guān)，了解AMPA受體的整個(gè)生命過(guò)程有助于進(jìn)一步認(rèn)識(shí)突觸可塑性,，進(jìn)而認(rèn)識(shí)學(xué)習(xí)記憶的分子機(jī)制,。
AMPA受體在粗面內(nèi)質(zhì)網(wǎng)合成，經(jīng)高爾基體修飾后,，更多地分布在樹(shù)突柄等非突觸部位,，LTP和CaMKⅡ可以啟動(dòng)AMPA受體的突觸插入，之后通過(guò)其胞質(zhì)內(nèi)C端,，由ABP,，GRIP和NSF等蛋白介導(dǎo)，錨定于突觸后致密斑。PICK1和PKC可以介導(dǎo)突觸膜上AMPA受體的胞吞過(guò)程,，離開(kāi)突觸后,，AMPA受體或被重新循環(huán)利用，或被溶酶體最終降解,。
離子型AMPA受體iGluRs在兩個(gè)學(xué)習(xí)和記憶的細(xì)胞模式：長(zhǎng)時(shí)程增強(qiáng)（long-term potentiation）和長(zhǎng)時(shí)程抑制（long-term depression）的誘導(dǎo)和維持過(guò)程中起著重要的作用。在這篇文章中,，研究人員利用一種稱(chēng)為X射線比較基因組雜交（X-array comparative genomic hybridization,，CGH）的技術(shù)，在編碼iGluR3的基因GRIA3上發(fā)現(xiàn)了一段基因組刪除（0.4 Mb）,，而且通過(guò)對(duì)帶有X-性染色體連鎖智力發(fā)育遲緩（X-linked mental retardation,，XLMR）的400個(gè)男性的測(cè)序發(fā)現(xiàn)了四個(gè)錯(cuò)義突變（missense variants）：G833R, M706T, R631S和R450Q。
進(jìn)一步的研究發(fā)現(xiàn)HEK293細(xì)胞中由于蛋白錯(cuò)誤折疊,，G833R會(huì)導(dǎo)致iGluR3減少78％,，同時(shí)研究人員也發(fā)現(xiàn)iGluR3-M706T(S2 domain)和iGluR3-R631S (near channel core)都不具有重要的通道功能，而R450Q (S1 domain)則與受體加速脫敏化（desensitization）有關(guān),。并且在HEK293細(xì)胞中在與iGluR2形成heteromeric receptors的時(shí)候,，這四種突變都會(huì)改變脫敏動(dòng)力學(xué)。
這些研究結(jié)果揭示了帶有可變動(dòng)力學(xué)特征的突變iGluR3與人類(lèi)中度認(rèn)知損傷（moderate cognitive impairment）有關(guān)的遺傳學(xué)和功能學(xué)特征,。
原始出處:
Published online before print November 7, 2007, 10.1073/pnas.0708699104
PNAS | November 13, 2007 | vol. 104 | no. 46 | 18163-18168
Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans
Ye Wua,b, Amy C. Araic, Gavin Rumbaughd,e, Anand K. Srivastavaf, Gillian Turnerg, Takashi Hayashid,e, Erika Suzukic, Yuwu Jianga,b, Lilei Zhanga, Jayson Rodriguezf, Jackie Boyleg, Patrick Tarpeyh, F. Lucy Raymondi, Joke Nevelsteenj, Guy Froyenj, Mike Strattonh, Andy Futrealh, Jozef Geczk, Roger Stevensonf, Charles E. Schwartzf, David Vallea, Richard L. Huganird,e, and Tao Wanga,l
aInstitute of Genetic Medicine and Department of Pediatrics, dDepartment of Neuroscience, and eHoward Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205; cDepartment of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62794; fGreenwood Genetic Center, Greenwood, SC 29646; gHunter Genetics and Genetics of Learning Disability (GOLD) Service, University of Newcastle, Callaghan NSW 2308, Australia; hWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom; iDepartment of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge CB2 2XY, United Kingdom; jHuman Genome Laboratory, Department of Human Genetics, Vlaams Instituut voor Biotechnologie, University of Leuven, 3000 Leuven, Belgium; kDepartment of Genetic Medicine, Women's and Children's Hospital, and Departments of Pediatrics and Molecular Biosciences, University of Adelaide, Adelaide SA 5005, Australia; and bDepartment of Pediatrics, Beijing University First Hospital, Beijing 100034, People's Republic of China
Communicated by C. Thomas Caskey, University of Texas–Houston Health Science Center, Houston, TX, September 14, 2007 (received for review May 16, 2007)
Ionotropic -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (iGluRs) mediate the majority of excitatory synaptic transmission in the CNS and are essential for the induction and maintenance of long-term potentiation and long-term depression, two cellular models of learning and memory. We identified a genomic deletion (0.4 Mb) involving the entire GRIA3 (encoding iGluR3) by using an X-array comparative genomic hybridization (CGH) and four missense variants (G833R, M706T, R631S, and R450Q) in functional domains of iGluR3 by sequencing 400 males with X-linked mental retardation (XLMR). Three variants were found in males with moderate MR and were absent in 500 control males. Expression studies in HEK293 cells showed that G833R resulted in a 78% reduction of iGluR3 due to protein misfolding. Whole-cell recording studies of iGluR3 homomers in HEK293 cells revealed that neither iGluR3-M706T (S2 domain) nor iGluR3-R631S (near channel core) had substantial channel function, whereas R450Q (S1 domain) was associated with accelerated receptor desensitization. When forming heteromeric receptors with iGluR2 in HEK293 cells, all four iGluR3 variants had altered desensitization kinetics. Our study provides the genetic and functional evidence that mutant iGluR3 with altered kinetic properties is associated with moderate cognitive impairment in humans.
glutamate receptor | X-linked mental retardation
