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排序方式: 共有120条查询结果,搜索用时 156 毫秒
61.
Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs 总被引:24,自引:0,他引:24
We describe a new class of drugs that selectively block serotonin M-receptors on peripheral neurones. Because of their high affinity, some of these drugs are the most potent of any pharmacological class yet reported. They have allowed the identification of three M-receptor subtypes, one of which is responsible for mediating the painful effects of serotonin in humans. 相似文献
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Baker M Mackenzie IR Pickering-Brown SM Gass J Rademakers R Lindholm C Snowden J Adamson J Sadovnick AD Rollinson S Cannon A Dwosh E Neary D Melquist S Richardson A Dickson D Berger Z Eriksen J Robinson T Zehr C Dickey CA Crook R McGowan E Mann D Boeve B Feldman H Hutton M 《Nature》2006,442(7105):916-919
Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival. 相似文献
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Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. 总被引:15,自引:0,他引:15
J A Piedrahita B Oetama G D Bennett J van Waes B A Kamen J Richardson S W Lacey R G Anderson R H Finnell 《Nature genetics》1999,23(2):228-232
Periconceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial, heart and neural tube defects. Although the underlying mechanism is unknown, there may be a maternal-to-fetal folate-transport defect or an inherent fetal biochemical disorder that is neutralized by supplementation. Previous experiments have identified a folate-binding protein (Folbp1) that functions as a membrane receptor to mediate the high-affinity internalization and delivery of folate to the cytoplasm of the cell. In vitro, this receptor facilitates the accumulation of cellular folate a thousand-fold relative to the media, suggesting that it may be essential in cytoplasmic folate delivery in vivo. The importance of an adequate intracellular folate pool for normal embryogenesis has long been recognized in humans and experimental animals. To determine whether Folbp1 is involved in maternal-to-fetal folate transport, we inactivated Folbp1 in mice. We also produced mice lacking Folbp2, another member of the folate receptor family that is GPI anchored but binds folate poorly. Folbp2-/- embryos developed normally, but Folbp1-/- embryos had severe morphogenetic abnormalities and died in utero by embryonic day (E) 10. Supplementing pregnant Folbp1+/- dams with folinic acid reversed this phenotype in nullizygous pups. Our results suggest that Folbp1 has a critical role in folate homeostasis during development, and that functional defects in the human homologue (FOLR1) of Folbp1 may contribute to similar defects in humans. 相似文献
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One of the most important inhibitory modulators of synaptic transmission in mammalian brain is adenosine. At some cholinergic terminals, adenosine is known to inhibit further release of acetylcholine. It is unclear whether adenosine is released directly at the synapse or whether ATP is co-released with transmitter and hydrolysed to adenosine in the synaptic cleft. Methods used in the past for isolating nerve terminals have not yielded homogeneous preparations, making it impossible to determine whether sufficient ATP or adenosine is released at specific synapses for inhibition of transmitter release to occur. Immunoaffinity purification techniques have recently permitted the preparation of homogeneous populations of cholinergic nerve terminals, which release ATP upon stimulation. We now report that in immunoisolated cholinergic nerve terminals from the striatum synaptic ectophosphohydrolases convert this ATP to adenosine, which inhibits further acetylcholine release, but this inhibitory effect is not seen in cortical cholinergic terminals lacking the complete ectophosphohydrolase pathway. Therefore the differing adenosine-mediated modulation in different brain areas is controlled by the presence and activity of synaptic ectophosphohydrolases. 相似文献
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