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G-protein beta gamma-subunits activate the cardiac muscarinic K+-channel via phospholipase A2 总被引:32,自引:0,他引:32
Muscarinic receptors of cardiac pacemaker and atrial cells are linked to a potassium channel (IK.ACh) by a pertussis toxin-sensitive GTP-binding protein. The dissociation of G-proteins leads to the generation of two potential transducing elements, alpha-GTP and beta gamma. IK.ACh is activated by G-protein alpha- and beta gamma-subunits applied to the intracellular surface of inside-out patches of membrane. beta gamma has been shown to activate the membrane-bound enzyme phospholipase A2 in retinal rods. Arachidonic acid, which is produced from the action of phospholipase A2 on phospholipids, is metabolized to compounds which may act as second messengers regulating ion channels in Aplysia. Muscarinic receptor activation leads to the generation of arachidonic acid in some cell lines. We therefore tested the hypothesis that beta gamma activates IK.ACh by stimulation of phospholipase A2. When patches were first incubated with antibody that blocks phospholipase A2 activity, or with the lipoxygenase inhibitor, nordihydroguaiaretic acid, beta gamma failed to activate IK.ACh. Arachidonic acid and several of its metabolites derived from the 5-lipoxygenase pathway, activated the channel. Blockade of the cyclooxygenase pathway did not inhibit arachidonic acid-induced channel activation. We conclude that the beta gamma-subunit of G-proteins activates IK.ACh by stimulating the production of lipoxygenase-derived second messengers. 相似文献
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A human homologue of the yeast HDEL receptor 总被引:51,自引:0,他引:51
Retention of resident proteins in the lumen of the endoplasmic reticulum is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi, or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually Lys-Asp-Glu-Leu (KDEL in the single letter code) in animal cells, His-Asp-Glu-Leu (HDEL) in Saccharomyces cerevisiae. There is evidence that the ERD2 gene encodes the sorting receptor that recognizes HDEL in yeast; its product is an integral membrane protein of relative molecular mass 26,000 (26K) that is not glycosylated. In contrast, Vaux et al. suggest that the mammalian KDEL receptor is a 72K glycoprotein that they detected using an anti-idiotypic antibody approach. If this were so, it would indicate a surprising divergence of the retrieval machinery between yeast and animal cells. We report here that human cells express a protein similar in sequence, size and properties to the ERD2 product, and propose that this protein is the human KDEL receptor. 相似文献
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However "just" it might be to credit LeConte, 1828, with Siren intermedia, both Harlan, 1826 (not 1827 as often cited), and Barnes, 1826, antedate LeConte's proposal of the name. As the earliest, Barnes, 1826, stands credited with it. In analysis of precedent for these conclusions, types of taxonomic plagiarism (calculated vs. innocent, homoplagiarism vs. heteroplagiarism) and the distinctions between nomina nuda and nomina dubia are reviewed, giving examples of each category. 相似文献
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Neale BM Kou Y Liu L Ma'ayan A Samocha KE Sabo A Lin CF Stevens C Wang LS Makarov V Polak P Yoon S Maguire J Crawford EL Campbell NG Geller ET Valladares O Schafer C Liu H Zhao T Cai G Lihm J Dannenfelser R Jabado O Peralta Z Nagaswamy U Muzny D Reid JG Newsham I Wu Y Lewis L Han Y Voight BF Lim E Rossin E Kirby A Flannick J Fromer M Shakir K Fennell T Garimella K Banks E Poplin R Gabriel S DePristo M Wimbish JR Boone BE Levy SE Betancur C Sunyaev S Boerwinkle E Buxbaum JD Cook EH Devlin B 《Nature》2012,485(7397):242-245
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors. 相似文献
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Pennacchio LA Ahituv N Moses AM Prabhakar S Nobrega MA Shoukry M Minovitsky S Dubchak I Holt A Lewis KD Plajzer-Frick I Akiyama J De Val S Afzal V Black BL Couronne O Eisen MB Visel A Rubin EM 《Nature》2006,444(7118):499-502
Identifying the sequences that direct the spatial and temporal expression of genes and defining their function in vivo remains a significant challenge in the annotation of vertebrate genomes. One major obstacle is the lack of experimentally validated training sets. In this study, we made use of extreme evolutionary sequence conservation as a filter to identify putative gene regulatory elements, and characterized the in vivo enhancer activity of a large group of non-coding elements in the human genome that are conserved in human-pufferfish, Takifugu (Fugu) rubripes, or ultraconserved in human-mouse-rat. We tested 167 of these extremely conserved sequences in a transgenic mouse enhancer assay. Here we report that 45% of these sequences functioned reproducibly as tissue-specific enhancers of gene expression at embryonic day 11.5. While directing expression in a broad range of anatomical structures in the embryo, the majority of the 75 enhancers directed expression to various regions of the developing nervous system. We identified sequence signatures enriched in a subset of these elements that targeted forebrain expression, and used these features to rank all approximately 3,100 non-coding elements in the human genome that are conserved between human and Fugu. The testing of the top predictions in transgenic mice resulted in a threefold enrichment for sequences with forebrain enhancer activity. These data dramatically expand the catalogue of human gene enhancers that have been characterized in vivo, and illustrate the utility of such training sets for a variety of biological applications, including decoding the regulatory vocabulary of the human genome. 相似文献
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