Bafilomycin A1 activates respiration of neuronal cells via uncoupling associated with flickering depolarization of mitochondria

Bafilomycin A1 (Baf) induces an elevation of cytosolic Ca²⁺ and acidification in neuronal cells via inhibition of the V-ATPase. Also, Baf uncouples mitochondria in differentiated PC12 (_dPC12), _dSH-SY5Y cells and cerebellar granule neurons, and markedly elevates their respiration. This respiratory response in _dPC12 is accompanied by morphological changes in the mitochondria and decreases the mitochondrial pH, Ca²⁺ and ΔΨm. The response to Baf is regulated by cytosolic Ca²⁺ fluxes from the endoplasmic reticulum. Inhibition of permeability transition pore opening increases the depolarizing effect of Baf on the ΔΨm. Baf induces stochastic flickering of the ΔΨm with a period of 20 ± 10 s. Under conditions of suppressed ATP production by glycolysis, oxidative phosphorylation impaired by Baf does not provide cells with sufficient ATP levels. Cells treated with Baf become more susceptible to excitation with KCl. Such mitochondrial uncoupling may play a role in a number of (patho)physiological conditions induced by Baf.     

Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome.

Thiamine-responsive megaloblastic anaemia syndrome (TRMA; MIM 249270) is an autosomal recessive disorder with features that include megaloblastic anaemia, mild thrombocytopenia and leucopenia, sensorineural deafness and diabetes mellitus. Treatment with pharmacologic doses of thiamine ameliorates the megaloblastic anaemia and diabetes mellitus. A defect in the plasma membrane transport of thiamine has been demonstrated in erythrocytes and cultured skin fibroblasts from TRMA patients. The gene causing TRMA was assigned to 1q23.2-q23.3 by linkage analysis. Here we report the cloning of a new gene, SLC19A2, identified from high-through-put genomic sequences due to homology with SLC19A1, encoding reduced folate carrier 1 (refs 8-10). We cloned the entire coding region by screening a human fetal brain cDNA library. SLC19A2 encodes a protein (of 497 aa) predicted to have 12 transmembrane domains. We identified 2 frameshift mutations in exon 2. a 1-bp insertion and a 2-bp deletion, among four Iranian families with TRMA. The sequence homology and predicted structure of SLC19A2, as well as its role in TRMA, suggest that its gene product is a thiamine carrier, the first to be identified in complex eukaryotes.     

A family of mammalian Na+-dependent L-ascorbic acid transporters.

Vitamin C (L-ascorbic acid) is essential for many enzymatic reactions, in which it serves to maintain prosthetic metal ions in their reduced forms (for example, Fe2+, Cu+), and for scavenging free radicals in order to protect tissues from oxidative damage. The facilitative sugar transporters of the GLUT type can transport the oxidized form of the vitamin, dehydroascorbic acid, but these transporters are unlikely to allow significant physiological amounts of vitamin C to be taken up in the presence of normal glucose concentrations, because the vitamin is present in plasma essentially only in its reduced form. Here we describe the isolation of two L-ascorbic acid transporters, SVCT1 and SVCT2, from rat complementary DNA libraries, as the first step in investigating the importance of L-ascorbic acid transport in regulating the supply and metabolism of vitamin C. We find that SVCT1 and SVCT2 each mediate concentrative, high-affinity L-ascorbic acid transport that is stereospecific and is driven by the Na+ electrochemical gradient. Despite their close sequence homology and similar functions, the two isoforms of the transporter are discretely distributed: SVCT1 is mainly confined to epithelial systems (intestine, kidney, liver), whereas SVCT2 serves a host of metabolically active cells and specialized tissues in the brain, eye and other organs.     

Renin in mouse but not in rat submandibular glands

Renin was found in the submandibular glands of male Quackenbush mice in concentrations higher than has been reported for any tissue of any strain or species. However, no renin-like activity could e detected in glands from male and female Wistar rats using either pH 5.8 or 7.4 for assay and a radioimmunoassay specific for renin's reaction product, angiotensin I. Rabbit submandibular glands contained renin.     

药物发现的先驱者格特鲁德B·埃利昂(1918～1999)

G·B·埃利昂（CertrudeBelleElion）是本世纪获得诺贝尔生理学与医学奖仅有6位女性中的一位。尽管这位合理药物设计的先驱完全应该为自己所取得的成就感到骄傲，但她一点不关心这类华丽词藻和周围气氛。她真正关心的是她认为会对疾病本身产生最有效治疗的最好技术。从她1983年退休到1999年2月21日81岁时突然去世为止，实际上她从未停止过工作，有不少人已认识到，她只是表面上退休而已。G·B·埃利昂1918年出生于纽约，她的父母来自立陶宛和俄罗斯。在10岁时她的祖父和母亲死于癌症，这是她记忆中印象最深刻的事件。1937年她从亨特女子…