http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Lim, Sangmi,Naisbitt, Scott,Yoon, Jiyoung,Hwang, Jong-Ik,Suh, Pann-Ghill,Sheng, Morgan,Kim, Eunjoon 부산대학교 유전공학연구소 1999 분자생물학 연구보 Vol.15 No.-
Shank1, Shank2, and Shank3 constitute a family of proteins that may funation as molecular scaffolds in the postsynaptic density (PSD). Shank directly interacts with GKAP and Homer, thus potentially bridging the N-methyl-D-aspartate receptor-PSD-95-GKAP complex and the mGluR-Homer complex in synapses (Naisbitt, S., Kim, E., Tu, J. C., Xiao, B., Sala, S., Valtschanoff, J., Weinberg, R. J., Worley, P. F., and Sheng, M. (1999) Neuron 23, 569-582; Tu, J. C., Xiao, B., Naisbitt, S., Yuan, J. P., Petralia, R. S., Brakeman, P., Doan, A., Askalu, V. K., Lanahan, A. A., Sheng, M., and Worley, P. F. (1999) Neuron 23, 583-592). Shank contains multiple domains for protein-protein interaction including ankyrin repeates, an SH3 domain, a PSD-95/Dlg/ZO-1 domain, a sterile α motif domain, and a proline-rich region. By characterizing Shank cDNA clones and RT-PCR products, we found that there are four sites for alternative splieing in Shank1 and another four sites in Shank2, some of ehich result in deletion of specific domains of the Shank protein. In addition, the expression of the splice variants is differentially regulated in different regions of rat brain during development. Immunoblot analysis of Shank proteins in rat brain using five different Shank antibodies reveals marked heterogeneity in size (120-240 kDa) and differential spatiotemporal expression. Shank1 immunoreactivity is concentrated at excitatory synaptic sites in adult brain, and the punctate staining of Shank1 is seen in developing rat brains as early as postnatal day 7. These results suggest that alternative splicing in the Shank family may be a mechanism that regulates the molecular structure of Shank and the spectrum of Shank-interaction proteins in the PSDs of adult and developing brain.
Naisbitt, Scott,Kim, Eunjoon,Weinberg, Richard J.,Rao, Anuradha,Yang, Fu-Chia,Craig, Ann Marie,Sheng, Morgan 부산대학교 유전공학연구소 1997 분자생물학 연구보 Vol.13 No.-
The structure of central synapses in poorly understood at the molecular level. A recent advance came with the identification of the postsynaptic density-95(PSD-95)/synapse-associated protein 90 family of proteins as important mediators of the synaptic clustering of certain classes of ion channels, By yeast two-hybrid screening, a novel oritein termed guanylate kinase-associated protein(GKAP) has been isolated that binds to the GK-like domain of PSD-95(Kim et al.,1997). Here we present a detailed characterization of GKAP expression in the rat brain and report the cloning of a novel GKAP splic variant. By Northern blot,GKAP mRNAs(4,6.5,and 8kB) are expressed predominantly in the rat brain. By in situ hydridization,GKAP is expressed widely in neurons of cortex and hippocampus and in the Purkinje and granule cells of the cerebellum. On brain immunoblots, two prominent bands of 95 and 130 kDa are detected that correspond to products of short and long N-terminal splic variants of GKAP. Two independent GKAP antibodies label somatodendritic puncta in neocortical and hippocampal neurons in a pattern consistent with synaptic elements. Immunogold electron microscopy reveals GKAP to be predominantly postsynptic and present at asymmetric synapses and in dendritic spines. The distribution of GKAP immunogold particles is uniform in the lateral plane of the PSD but peaks in the perpendicular axis∼20nm from the postsynaotic menbrane. In cultured hippocampal neurons GKAP immunoreactive puncta colocalize with the AMPA receptor subunit Glu receptor 1 but not with the GABA_A receptor subunil β2and β3. Thus GKAP is a widely expressed neuronal protein localized specifically in the PSD of glutamatergic synapses, consistent with its direct interaction with PSD-95 family proteins.
Kim, Eunjoon,Naisbitt, Scott,Hsueh, Yi-Ping,Rao, Anuradha,Rothschild, Adam,Graig, Ann Marie,Sheng, Morgan 부산대학교 유전공학연구소 1997 분자생물학 연구보 Vol.13 No.-
The molecular mechanisms underlying the organization of ion channels and signsling molecules at the synaptic junction are largely unknown. Recently, members of the PSD-95/SAP90 family of synaptic MAGUK(menbrane-acssociated guanylate kinase) proteins have been shown to interact. via their NH_2-terminal PDZ domains, with certain ion channels(NMDA receptors and K^+channels). thereby promoting the clustering of these proteins. Although the function of the NH_2-terminal PDZ domains in relatively well characterized, the function of the Src homology 3(SH3) domain and the guanylate kinase-like(GK)domain in the COOH-terminal half of PSD-95 has remained obscure. WE now repoet the isolation of a novel synaptic protein. termed GKAP for guanylate kinase-associated protein. that binds directly to the GK domain of the known members of the mammalian PSD-95 family. GKAP shows a unique domain structure and appear to be a major constituent of the postsynaptic density. GKAP colocalizes and coimmunoprecipitates with PSD-95 in vivo,and colusters with PSD-95 and K^+ channels/parent lack of guanylate kinase enzymatic activity, the fact that the GK domain can as a site for protein-protein interaction has implications for the function of diverse GK-containing proteins(such as p55,ZO-1,and LIN-2/CASK).
Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury
김승현,Dean J. Naisbitt 대한천식알레르기학회 2016 Allergy, Asthma & Immunology Research Vol.8 No.1
Drug-induced liver injury (DILI) is a major concern for public health, as well as for drug development in the pharmaceutical industry, since it can cause liver failure and lead to drug withdrawal from the market and black box warnings. Thus, it is important to identify biomarkers for early prediction to increase our understanding of mechanisms underlying DILI that will ultimately aid in the exploration of novel therapeutic strategies to prevent or manage DILI. DILI can be subdivided into ‘intrinsic’ and ‘idiosyncratic’ categories, although the validity of this classification remains controversial. Idiosyncratic DILI occurs in a minority of susceptible individuals with a prolonged latency, while intrinsic DILI results from drug- induced direct hepatotoxicity over the course of a few days. The rare occurrence of idiosyncratic DILI requires multicenter collaborative investigations and phenotype standardization. Recent progress in research on idiosyncratic DILI is based on key developments in 3 areas: (1) newly developed high-throughput genotyping across the whole genome allowing for the identification of genetic susceptibility markers, (2) new mechanistic concepts on the pathogenesis of DILI revealing a key role of drug-responsive T lymphocytes in the immunological response, and (3) broad multidisciplinary approaches using different platform “-omics” technologies that have identified novel biomarkers for the prediction of DILI. An association of a specific human leukocyte antigen (HLA) allele with DILI has been reported for several drugs. HLA-restricted T-cell immune responses have also been investigated using lymphocytes and T-cell clones isolated from patients. A microRNA, miR-122, has been discovered as a promising biomarker for the early prediction of DILI. In this review, we summarize recent advances in research on idiosyncratic DILI with an understanding of the key role of adaptive immune systems.