ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2714568

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Nimodipine, a Ca2+antagonist with cerebrovasodilatory and anti‐ischemic effects, binds to rat, guinea pig, and human brain membranes with high affinity (less than 1 nM). Only at higher concentrations has nimodipine been reported to block the release of some neurotransmitters and hormones from neuronal tissue. Nimodipine has no consistent effect on brain oxygen consumption or cortical ATP or phosphocreatine levels, although the ischemia‐induced fall of brain ATP levels in gerbils or the lowering of intracellular brain pH in rabbits with focal cerebral ischemia were antagonized by the drug. In rats and baboons with middle cerebral artery occlusion, nimodipine was found to reduce neurological deficits without an increase in intracranial pressure or brain edema. Electrophysiological studies with nimodipine suggested a direct neuronal action. In rabbit dorsal root ganglion cells, concentrations as low as 20 nM were reported to block inward Ca2+currents. Recent studies have suggested that nimodipine may also improve memory in brain‐damaged or old rats, restore sensorimotor function and abnormal walking patterns of old rats, and accelerate acquisition of associative learning in aging rabbits. Blockade of age‐related changes in Ca2+fluxes in rat hippocampal neurones by nimodipine in vitro pointed to neuronal plasma membrane as the site of nimodipine action. The therapeutic usefulness of nimodipine appears not to be limited to cerebral ischemia, but may include dementia, age‐related degenerative diseases, epilepsy, and ethanol intoxication.—Scriabine, A.; Schuurman, T.; Traber, J. Pharmacological basis for the use of nimodipine in central nervous system disorders.FASEB J.3: 1799‐1806; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2565839

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Brevetoxins are lipid‐soluble polyether marine toxins of unique structure and pharmacological function. Toxins are active in vivo in the nanomolar to picomolar concentration range and in vitro in isolated neuromuscular or giant axon preparations and in single‐cell or subcellular model systems. Their effect is excitatory, mediated by the enhancement of cellular Na+influx. Brevetoxins bind at site 5 on the voltage‐sensitive sodium channel, a specificity shared with ciguatoxin. This site is allosterically linked to other natural toxin binding sites on the channel.—Baden, D. G. Brevetoxins: unique polyether dinoflagellate toxins.FASEB J.3: 1807‐1817; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2565840

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

The hallmark of the immune system is its ability to produce a seemingly infinite variety pf antigen‐binding receptors. This is made possible by molecular and cellular mechanisms uniquely suited to continuously generate a large number of individual receptor molecules and to select some for further expansion. The well‐studied genetic rearrangement that results in the juxtaposition of germ line‐encoded variable, diversity, and joining elements remains the foundation for diversification on which the repertoire is built. Many of the rules that regulate this phenomenon have been described, although the underlying enzymatic machinery responsible for these events remains to be elucidated. Recent progress in categorizing the immunoglobulin heavy‐chain variable region genes into families as well as studies establishing their utilization in both fetal and adult life is helping to further refine these rules. Subsequent cellular interactions1) permit the discriminant expansion of clones expressing relevant antibody molecules,2) allow the active affinity alterations needed for effective ongoing immune responses, and3) limit the potential deleterious effect of autoreactive cells.— Paige, C. J.; Wu, G. E. The B cell repertoire.FASEB J.1818‐1824; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2497040

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Receptors that mediate their actions by stimulating guanine nucleotide binding regulatory proteins (G proteins) share structural as well as functional similarities. The structural motif characteristic of receptors of this class includes seven hydrophobic putative transmembrane domains linked by hydrophilic loops. Genetic analysis of the β‐adrenergic receptor (βAR) revealed that the ligand binding domain of this receptor, like that of rhodopsin, involves residues within the hydrophobic core of the protein. On the basis of these studies, a model for ligand binding to the receptor has been developed in which the amino group of an agonist or antagonist is anchored to the receptor through the carboxylate side chain of Asp113in the third transmembrane helix. Other interactions between specific residues of the receptor and functional groups on the ligand have also been proposed. The interaction between the βAR and the G protein Gshas been shown to involve an intracellular region that is postulated to form an amphi‐philic α helix. This region of the βAR is also critical for sequestration, which accompanies agonist‐mediated desensitization, to occur. Structural similarities among G protein‐linked receptors suggest that the information gained from the genetic analysis of the βAR should help define functionally important regions of other receptors of this class.— Strader, C. D.; Sigal, I. S.; Dixon, R. A. F. Structural basis of β‐adrenergic receptor function.FASEB J.3: 1825‐1832; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2541037

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Recent studies of structure‐function relationships in biological membranes have revealed fundamental concepts concerning the regulation of cellular membrane function by membrane lipids. Considerable progress has been made in understanding the roles played by two membrane lipids: cholesterol and phosphatidylethanolamine. Cholesterol has been shown to regulate ion pumps, which in some cases show an absolute dependence on cholesterol for activity. These studies suggest that an essential role that cholesterol plays in mammalian cell biology is to enable crucial membrane enzymes to provide function necessary for cell survival. Studies of phosphatidylethanolamine regulation of membrane protein activity and regulation of membrane morphology led to hypotheses concerning the roles for this particular lipid in biological membranes. New information on lipid‐protein interactions and on the nature of the lipid head groups has permitted the development of mechanistic hypotheses for the regulation of membrane protein activity by phosphatidylethanolamine. In addition, intermediates in the lamellarnonlamellar phase transitions of membrane systems containing phosphatidylethanolamine, or other lipids with similar properties, have recently been implicated in facilitating membrane fusion. Finally, studies of transmembrane movement of lipids have provided new insight into the regulation of membrane lipid asymmetry and the biogenesis of cell membranes. These kinds of studies are harbingers of a new generation of progress in the field of cell membranes.—Yeagle, P. L. Lipid regulation of cell membrane structure and function.FASEB J.3: 1833‐1842; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2469614

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Glucocorticoid hormones kill immature thymocytes by activating a self‐destructive process that involves extensive DNA fragmentation. It has been demonstrated that thymocyte suicide is dependent on an early, sustained increase in cytosolic Ca2+concentration, and new protein synthesis, but the biochemical lesion that leads to cell death has not been established. To determine whether endonuclease activation or activation of another Ca2+‐de‐pendent process could mediate cell killing, we treated thymocytes with the glucocorticoid methylprednisolone in the presence of inhibitors of various Ca2+‐dependent degradative enzymes. The role of poly(ADP‐ribose) polymerase, an enzyme known to be activated by DNA damage, was also assessed. Glucocorticoid‐induced chromatin cleavage and cell killing were blocked by the endonuclease inhibitor aurintricarboxylic acid, whereas inhibitors of other Ca2+‐dependent degradative processes or of poly(ADP‐ribose) polymerase did not abrogate cell death. In addition, stimulation of thymocyte DNA fragmentation by the Ca2+ionophore A23187 resulted in cell killing that could be blocked by the endonuclease inhibitor. Together, our results suggest that thymocyte suicide is caused by extensive Ca2+‐stimulated DNA fragmentation.— McConkey, D. J.; Hartzell, P.; Nicotera, P.; Orrenius, S. Calcium‐activated DNA fragmentation kills immature thymocytes.FASEB J.3: 1843‐1849; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2497041

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

The effects of halothane, isoflurane, and enflurane on ionic currents induced by bath application of γ‐aminobutyric acid (GABA) were studied with the rat dorsal root ganglion neurons maintained in primary culture. The whole‐cell patch clamp technique was used to record the current. In normal neurons before exposure to anesthetics, GABA at low concentrations (1‐3 times 10−6M) induced a small sustained inward current. At higher concentrations (3 times 10−5M‐1 times 10−3M), GABA induced a large inward current, which decayed to a steady‐state level (desensitization). Halothane (0.86 mM), isoflurane (0.96 mM), and enflurane (1.89 mM), each equivalent to the respective 2 minimum alveolar concentration (MAC) units, augmented the sustained current evoked by 3 times 10−6M GABA to 330‐350% of control and the peak current evoked by 3 times 10−5M of GABA to 136‐145% of control. The decay phase of the current was accelerated by the anesthetics, the time for the current to decline to 70% of the peak being reduced to 23‐39% of control. In contrast, the desensitized steady‐state current evoked by high concentrations of GABA was decreased by anesthetics. In conclusion, general anesthetics exert a dual effect on the GABA receptor channel complex: to potentiate the nondesensitized (both peak and sustained) current and to suppress the desensitized steady‐state current. The potentiation of the GABA receptor channel response may be a primary action of anesthetics leading to surgical anesthesia.—Nakahiro, M.; Yeh, J. Z.; Brunner, E.; Narahashi, T. General anesthetics modulate GABA receptor channel complex in rat dorsal root ganglion neurons.FASEB J.3: 1850‐1854; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2541038

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Xylitol is known to cause hepatic ATP catabolism by inducing the trapping of Piin the form of glycerol 3‐P as a consequence of an increase in the NADH:NAD+ratio, resulting from the oxidation of xylitol tod‐xylulose. The question was therefore raised whetherd‐xylulose also depletes hepatic ATP. In isolated rat hepatocytes, 5 mMd‐xylulose decreased ATP by 80% within 5 min compared to 40% with 5 mM xylitol. Intracellular Pidecreased by 70% within the same time interval with both compounds, but was restored threefold faster withd‐xylulose. The rate of utilization ofd‐xylulose reached 5 μmol · min−1· g−1of cells, as compared with 1.5 for xylitol, indicating that reduction of xylitol intod‐xylulose is a rate‐limiting step in the metabolism of the polyol.d‐Xylulose barely modified the concentration of glycerol 3‐P but increased xylulose 5‐P from 0.02 to 0.5 μmol/g within 5 min. The main cause of the ATP‐ and Pi‐depleting effects ofd‐xylulose was found to be an accumulation of sedoheptulose 7‐P from a basal value of 0.1 to 5 μmol/g of cells after 10 min. Ribose 5‐P increased from 0.03 to 0.5 μmol/g at 5 min. Ribose 1‐P also accumulated, albeit outside of the cells. This extracellular accumulation can be explained by the release of intracellular purine nucleoside phosphorylase from damaged hepatocytes acting on inosine that had diffused out of the cells. Smaller increases in the concentrations of sedoheptulose 7‐P and pentose phosphates were recorded after incubations of the cells with xylitol.—Vincent, M. F.; VandenBerghe, G.; Hers, H‐G.d‐Xyluloseinduced depletion of ATP and Piin isolated rat hepatocytes.FASEB J.3: 1855‐1861; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2523832

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

A series of compounds that induce depletion of ATP and Piwhen added to isolated rat hepatocytes were found to cause a remarkable, although transient, elevation in the concentration of phosphoribosyl pyrophosphate (PRPP) in these cells. After the addition of 5 mM fructose, xylitol, tagatose, ord‐xylulose, PRPP increased from a basal value of 6 ± 1 nmol/g of cells to, respectively, 68 ± 11, 42 ± 11, 67 ± 22, and 530 ± 50 nmol/g of cells (means ± SEM of 3‐9 experiments). In each case, the increase in PRPP was preceded by a latency period of 5‐10 min. PRPP reached maximal levels 15 min after the addition of fructose and 30 min after that of xylitol andd‐xylulose, but continued to increase for as long as 60 min after the addition of tagatose. Most striking was that the increase in PRPP closely paralleled the restoration of intracellular Pi. Ribose 5‐P increased about two‐ to fivefold after the addition of fructose, xylitol, and tagatose, and approximately 12‐fold afterd‐xylulose. The mechanism by which ATP‐ and Pi‐depleting compounds stimulate the activity of PRPP synthetase in isolated rat hepatocytes is discussed.—Vincent, M. E.; VandenBerghe, G.; Hers, H‐G. Increase in phosphoribosyl pyrophosphate induced by ATP and Pidepletion in hepatocytes.FASEB J.3: 1862‐1867; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.7.2469615

出版商:Wiley    

年代:1989

数据来源: WILEY