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61.
The treatment of 6-phosphogluconate dehydrogenase from Candida utilis with dansyl chloride causes the modification of one amino acid residue per enzyme subunit and the inactivation of the enzyme. Either a cysteine or a tyrosine residue can be modified, depending on the pH of the reaction mixture. The dansyl residue can be transferred from one residue to the other suggesting that the two amino acid residues are close in the tridimensional structure of the active site of the enzyme.  相似文献   
62.
Tertiary amine local anesthetics (dibucaine, Tetracaine, procaine, etc.) modify cell morphology, concanavalin A (Con A)-mediated agglutinability and redistribution of Con A receptors. Con A agglutination of untransformed mouse 3T3 cells was enhanced at low concentrations of local anesthetics, and the dynamics of fluorescent-Con A indicated that ligand-induced clustering was increased in the presence of the drugs. In contast, these drugs inhibited Con A-induced receptor capping on mouse spleen cells. These effects can be duplicated by combinations of vinblastine (or colchicine) and cytochalasin B suggesting that local anesthetics act on microtubule cell surface receptor mobility and distribution. It is proposed that tertiary amine local anesthetics displace plasma membrane-bond Ca2+, resulting in disengagement of microfilament systems from the plasma membrane and increased cellular Ca2+ concentration to levels which disrupt microtubular organization. The possible involvement of cellular Ca2+ in cytoskeletal destruction by local anesthetics was investigated utilizing Ca2+-specific ionophores A23187 and X537A. In media containing Ca2+ and cytochalasin B these ionophores caused effects similar to tertiary amine local anesthetics.  相似文献   
63.
Summary The presence of uni-, bi- and multipolar neurons beneath the hair cell epithelium of the Octopus gravity receptor system has been demonstrated by iontophoretic cobalt staining. Counts give an average number of 1,940 neurons per macula. Whether the hair cells are primary of secondary sensory cells is discussed.This work was supported by grant Wo 160/3 of the Deutsche Forschungsgemeinschaft (DFG) to H.G.W. Thanks are due to the Director and staff of the Zoological Station in Naples for their hospitality and help  相似文献   
64.
65.
Ion channels are integral membrane proteins whose gating has been increasingly shown to depend on the presence of the low-abundance membrane phospholipid, phosphatidylinositol (4,5) bisphosphate. The expression and function of ion channels is tightly regulated via protein phosphorylation by specific kinases, including various PKC isoforms. Several channels have further been shown to be regulated by PKC through altered surface expression, probability of channel opening, shifts in voltage dependence of their activation, or changes in inactivation or desensitization. In this review, we survey the impact of phosphorylation of various ion channels by PKC isoforms and examine the dependence of phosphorylated ion channels on phosphatidylinositol (4,5) bisphosphate as a mechanistic endpoint to control channel gating.  相似文献   
66.
The molecular mechanisms underlying the anterograde surface transport of G protein–coupled receptors (GPCRs) after their synthesis in the endoplasmic reticulum (ER) are not well defined. In C. elegans, odorant response abnormal 4 has been implicated in the delivery of olfactory GPCRs to the cilia of chemosensory neurons. However, the function and regulation of its human homolog, C1orf27, in GPCR transport or in general membrane trafficking remain unknown. Here, we demonstrate that siRNA-mediated knockdown of C1orf27 markedly impedes the ER-to-Golgi export kinetics of newly synthesized α2A-adrenergic receptor (α2A-AR), a prototypic GPCR, with the half-time being prolonged by more than 65%, in mammalian cells in retention using the selective hooks assays. Using modified bioluminescence resonance energy transfer assays and ELISAs, we also show that C1orf27 knockdown significantly inhibits the surface transport of α2A-AR. Similarly, C1orf27 knockout by CRISPR-Cas9 markedly suppresses the ER–Golgi-surface transport of α2A-AR. In addition, we demonstrate that C1orf27 depletion attenuates the export of β2-AR and dopamine D2 receptor but not of epidermal growth factor receptor. We further show that C1orf27 physically associates with α2A-AR, specifically via its third intracellular loop and C terminus. Taken together, these data demonstrate an important role of C1orf27 in the trafficking of nascent GPCRs from the ER to the cell surface through the Golgi and provide novel insights into the regulation of the biosynthesis and anterograde transport of the GPCR family members.  相似文献   
67.
Long-term activation of inositol 1,4,5-trisphosphate receptors (IP3Rs) leads to their degradation by the ubiquitin–proteasome pathway. The first and rate-limiting step in this process is thought to be the association of conformationally active IP3Rs with the erlin1/2 complex, an endoplasmic reticulum–located oligomer of erlin1 and erlin2 that recruits the E3 ubiquitin ligase RNF170, but the molecular determinants of this interaction remain unknown. Here, through mutation of IP3R1, we show that the erlin1/2 complex interacts with the IP3R1 intralumenal loop 3 (IL3), the loop between transmembrane (TM) helices 5 and 6, and in particular, with a region close to TM5, since mutation of amino acids D-2471 and R-2472 can specifically block erlin1/2 complex association. Surprisingly, we found that additional mutations in IL3 immediately adjacent to TM5 (e.g., D2465N) almost completely abolish IP3R1 Ca2+ channel activity, indicating that the integrity of this region is critical to IP3R1 function. Finally, we demonstrate that inhibition of the ubiquitin-activating enzyme UBE1 by the small-molecule inhibitor TAK-243 completely blocked IP3R1 ubiquitination and degradation without altering erlin1/2 complex association, confirming that association of the erlin1/2 complex is the primary event that initiates IP3R1 processing and that IP3R1 ubiquitination mediates IP3R1 degradation. Overall, these data localize the erlin1/2 complex–binding site on IP3R1 to IL3 and show that the region immediately adjacent to TM5 is key to the events that facilitate channel opening.  相似文献   
68.
An asymmetric synthetic strategy was designed for the preparation of the four possible diastereoisomers of 3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one, a non-steroidal FXR agonist, we recently discovered following a virtual screening approach. The results obtained from an AlphaScreen assay clearly demonstrated that only the isomer endowed with 4R,6S absolute configuration is responsible for the biological activity. A deep investigation of the different putative binding modes adopted by these enantiomerically pure ligands using computational modeling studies confirmed the enantioselectivity of FXR towards this class of molecules.  相似文献   
69.
本研究采用活性追踪的方法,逐步从人工培养蝉花虫草分离获得A(50%乙醇回流提取)、B(膜分离)、C(大孔树脂洗脱)和D(Sephadex LH20柱纯化)等4种样品,单一化合物D纯度为98.62%,鉴定为N6‐(2‐羟乙基)腺苷[N6‐(2‐hydroxyethyl)‐adenosine,HEA]。研究各样品对戊四唑(pentylenetetrazol,PTZ)诱导的小鼠惊厥模型的影响,以及选择性腺苷A1受体(AA1R)拮抗剂DPCPX或选择性腺苷A2A受体(AA2AR)拮抗剂ZM241385对HEA作用的影响,并采用苏木精-伊红(hematoxylin-eosin,HE)染色、免疫组化(immunohistochemical,IHC)染色和蛋白质免疫印迹(Western blot,WB)等技术进一步探究HEA抗惊厥作用的机制。结果表明,各样品(i.p.)均有抗惊厥活性,HEA(40–60mg/kg,i.p.)能显著延长惊厥小鼠的存活时间和降低死亡率,DPCPX(2mg/kg,i.p.)能够拮抗HEA的抗惊厥作用,而ZM241385无此作用;HE、IHC和WB的结果进一步揭示DPCPX显著降低HEA的作用。综上所述,蝉花虫草的HEA具有抗惊厥作用,并且可能通过激活腺苷A1受体而起作用。  相似文献   
70.
Nitrogen oxide-containing compounds displaced the peripheral benzodiazepine ligand [3H]Ro5-4864 from guinea pig membrane preparations. Sodium nitroprusside (SNP) was the most potent (IC50 = 5.61 ± 1.72 × 10−5 M). Moreover, its ability to bind to these receptors showed marked tissue variability (heart> kidney cerebral cortex). When tested on rat atrium, SNP by itself had no effect on basal inotropy or the increase in inotropy induced by (−)-S-BAY K 8644. In contrast, Ro5-4864 potentiated the marked increase in inotropy induced by (−)-S-Bay K 8644, and SNP completely abolished the potentiation of inotropy observed with Ro5-4864. Since peripheral benzodiazepine receptors are associated with calcium mobilization in the heart, these findings may indicate that some of the clinical effects of nitric oxide-generating drugs could be mediated by these receptors.  相似文献   
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