来自约翰霍普金斯医学院，霍德华休斯医学院遗传医学研究院，神经科学系，南伊利诺斯大学医学院，纽卡斯尔大学（The University of New Castle），北京大学第一附属医院等处的研究人员通过遗传学和功能学研究证明了带有可变动力学特征的突变iGluR3与人类中度认知损伤（moderate cognitive impairment）有关。这为了解代谢型谷氨酸受体AMPA受体的作用机理，以及深入研究学习和记忆的细胞模式提供了重要资料。这一研究成果公布在《美国国家科学院院刊》（PNAS）上。
文章的通讯作者是来自约翰霍普金斯医学院的王涛（Tao Wang，音译）副教授，第一作者是同属约翰霍普金斯和北京大学附属第一医院的吴叶（Ye Wu，音译）博士。
在大脑中难以计数的突触中，目前认为兴奋性突触执行着学习和认知的主要功能。谷氨酸是大脑中含量最多，功能最强的兴奋性突触递质。谷氨酸在突触后膜上的受体被受体特异性的激动剂分为几类，NMDA受体，AMPA受体和代谢型谷氨酸受体是最主要的三类。其中α-氨基-3-羟基-4异恶唑-丙酸（α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid，AMPA）受体与突触可塑性密切相关，了解AMPA受体的整个生命过程有助于进一步认识突触可塑性，进而认识学习记忆的分子机制。
AMPA受体在粗面内质网合成，经高尔基体修饰后，更多地分布在树突柄等非突触部位，LTP和CaMKⅡ可以启动AMPA受体的突触插入，之后通过其胞质内C端，由ABP，GRIP和NSF等蛋白介导，锚定于突触后致密斑。PICK1和PKC可以介导突触膜上AMPA受体的胞吞过程，离开突触后，AMPA受体或被重新循环利用，或被溶酶体最终降解。
离子型AMPA受体iGluRs在两个学习和记忆的细胞模式：长时程增强（long-term potentiation）和长时程抑制（long-term depression）的诱导和维持过程中起着重要的作用。在这篇文章中，研究人员利用一种称为X射线比较基因组杂交（X-array comparative genomic hybridization，CGH）的技术，在编码iGluR3的基因GRIA3上发现了一段基因组删除（0.4 Mb），而且通过对带有X-性染色体连锁智力发育迟缓（X-linked mental retardation，XLMR）的400个男性的测序发现了四个错义突变（missense variants）：G833R, M706T, R631S和R450Q。
进一步的研究发现HEK293细胞中由于蛋白错误折叠，G833R会导致iGluR3减少78％，同时研究人员也发现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)则与受体加速脱敏化（desensitization）有关。并且在HEK293细胞中在与iGluR2形成heteromeric receptors的时候，这四种突变都会改变脱敏动力学。
这些研究结果揭示了带有可变动力学特征的突变iGluR3与人类中度认知损伤（moderate cognitive impairment）有关的遗传学和功能学特征。
原始出处:
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
