ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.3308610

出版商:Wiley    

年代:1987

数据来源: WILEY

摘要:

The function of chloride (Cl−) channel proteins is to regulate the transport of Cl−across membranes. There are two major kinds of Cl−channels:1) those activated by binding of a transmitter such as γ‐aminobutyric acid (GABA), glycine, or glutamate, and thus are receptors; and2) those activated by membrane depolarization or by calcium. There are two kinds of GABA receptors: GABAAis the major inhibitory receptor of vertebrate brain and the one that operates a Cl−channel, and the GABABreceptor, which is proposed to regulate cAMP production that is stimulated by other receptors. Except for binding of GABA, these two GABA receptors differ completely in their drug specificities. However, there are many similarities among the GABAAreceptor, the glycine receptor, and the voltage‐dependent Cl−channel. The two receptors and Cl−channels bind avermectin, whereas bicuculline binds only to mammalian GABAAand glycine receptors, not to the insect brain GABAAreceptor. Barbiturates bind to GABAAand voltage‐dependent Cl−channels, possibly directly activating them. Benzodiazepines potentiate both the glycine and GABAAreceptors. Several insecticides act on the GABAAreceptor and voltage‐dependent Cl−channel. It is suggested that the GABAAreceptor is the primary target for the action of toxaphene and cyclodiene insecticides but a secondary target for lindane and type II pyrethroids. On the other hand, the Cl−channel may be a primary target for avermectin and lindane but a secondary one for cyclodienes. The similarity in certain drug specificities and the operation of Cl−channels suggest a degree of homology between the subunits of GABAAand glycine receptors and the voltage‐dependent Cl−channels.—Eldefrawi, A. T.; Eldefrawi, M. E. Receptors for γ‐aminobutyric acid and voltage‐dependent chloride channels as targets for drugs and toxicants.FASEB J.1: 262‐271; 1987.

ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.2443413

出版商:Wiley    

年代:1987

数据来源: WILEY

摘要:

The mesangial cell occupies a central position in the renal glomerulus. It has characteristics of a modified smooth muscle cell, but is also capable of a number of other functions. Among these are generation of prostaglandins (PGs) and mediators of inflammation; production and breakdown of basement membrane and other biomatrix material; synthesis of cytokines; and uptake of macromolecules, including immune complexes. In terms of its smooth muscle activity, the mesangial cell contracts or relaxes in response to a number of vasoactive agents. This ability allows the cells to modify glomerular filtration locally. The cellular mechanism of action of many agents influencing mesangial cells involves activation of phospholipase C for phosphatidylinositol 4,5‐bisphosphate. This results in generation of inositol trisphosphate and release of intracellular calcium. Mesangial cell relaxation can be mediated by enhanced cAMP or cGMP generation. Many vasoactive substances also stimulate PG production by mesangial cells. This involves activation of both phospholipase C and A2, the latter being responsible for the release of arachidonic acid. Mesangial cells are also capable of endocytosis of macromolecules, including immune complexes. This is initiated by binding to a specific receptor, resulting in formation of PG, platelet‐activating factor, and reactive oxygen species. Mesangial cells can generate interleukin 1 and platelet‐derived growth factor and respond to these in an autocrine manner. Thus, the mesangial cell not only can control glomerular filtration, but may also be involved in the response to local injury, including cell proliferation and basement membrane remodeling.— Schlondorff, D. The glomerular mesangial cell: an expanding role for a specialized pericyte.FASEB J.1: 272‐281; 1987.

ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.3308611

出版商:Wiley    

年代:1987

数据来源: WILEY

摘要:

The peripheral‐type benzodiazepine receptor is a site identified by its nanomolar affinity for [3H]diazepam, similar to the affinity of diazepam for the central‐type benzodiazepine receptor in the brain. The peripheral‐type benzodiazepine receptor occurs in many peripheral tissues but has discrete localizations as indicated by autoradiographic studies showing uniquely high densities of the receptors in the adrenal cortex and in Leydig cells of the testes. Subcellular localization studies reveal a selective association of the receptors with the outer membrane of mitochondria. Photoaffinity labeling of the mitochondrial receptor with [3H]flunitrazepam reveals two discrete labeled protein bands of 30 and 35 kDa, respectively. The 35‐kDa band appears to be identical with the voltage‐dependent anion channel protein porin. Fractionation of numerous peripheral tissues reveals a single principal endogenous ligand for the receptor, consisting of porphyrins, which display nanomolar affinity. Interactions of porphyrins with the mitochondrial receptor may clarify its physiological role and account for many pharmacological actions of benzodiazepines.—Snyder, S. H.; Verma, A.; Trifiletti, R. R. The peripheral‐type benzodiazepine receptor: a protein of mitochondrial outer membranes utilizing porphyrins as endogenous ligands.FASEB J.1: 282‐288; 1987.

ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.2820823

出版商:Wiley    

年代:1987

数据来源: WILEY

摘要:

Treatment with low physiological concentrations of epinephrine (5‐50 nM) rapidly desensitizes β‐adrenergic stimulation of cAMP formation in S49 wild‐type (WT) lymphoma cells. Previous attempts to detect this early phase of desensitization in cell‐free assays of adenylate cyclase (EC 4.6.1.1) after intact cell treatment were unsuccessful. We have now found that reducing the Mg2+concentrations in the adenylate cyclase assays to<1.0 mmunmasked this rapid phase of desensitization of the WT cells, and that high Mg2+concentrations (5‐10 mm) largely obscured the desensitization. Submillimolar Mg2+conditions also revealed a two‐ to threefold decrease in the affinity of epinephrine binding to the β‐adrenergic receptor after desensitization with 20 nmepinephrine. Detection of 4β‐phorbol 12‐myristate 13‐acetate (PMA) desensitization of the WT β‐adrencrgic receptor was also dependent on low Mg2+as measured either by the decrease in epinephrine stimulation of adenylate cyclase or by the reduction in the affinity of epinephrine binding. Unexpectedly, when cyc−cells were pretreated with 50 nmepinephrine, the β‐adrenergic stimulation of reconstituted adenylate cyclase was not desensitized. The characteristics of the Mg2+effect on epinephrine‐ and PMA‐induced desensitizations suggest a similar mechanism of action with the most likely events being phosphorylations of the β‐adrenergic receptors. Our data indicate that cAMP‐dependent protein kinase (EC 2.7.1.37) may play a role in the desensitization caused by low epinephrine concentrations inasmuch as this phase of desensitization did not occur in the cyc−. For the PMA‐induced desensitization, the phosphorylation may be mediated by protein kinase C (EC 2.7.1.37).—Clark, R. B.; Friedman, J.; Johnson, J. A.; Kunkel, M. W. β‐Adrenergic receptor desensitization of wild‐type but not cyc lymphoma cells unmasked by submillimolar Mg2+.FASEB J.1: 289‐297; 1987.

ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.2820824

出版商:Wiley    

年代:1987

数据来源: WILEY

摘要:

Soaking frog motor nerve terminals in a hypertonic solution produces an increase in the size of miniature end plate potentials (mepp's) and miniature end plate currents (mepc's) after the preparations are returned to normal Ringer's solution. There is substantial evidence that the size increase occurs because additional acetylcholine (ACh+) is incorporated into the quanta. It has been proposed that ACh+loading into synaptic vesicles requires a proton gradient. As a step in testing this hypothesis the effects of millimolar concentrations of NH4+, methylamine+, or trimethylamine+in the extracellular solution on the increase in quantal size were measured. These substances would be expected to accumulate in acid intracellular compartments, which would diminish the acidity. The increase in quantal size was blocked by these substances, in agreement with the idea that the proton gradient is involved in ACh+accumulation. Tetanic stimulation in solutions containing 5 mmNH4Cl also produces a decrease in quantal size, not seen in controls in NH4+‐free solution. The inhibition of transmitter packaging by ammonia may play a role in the neural sequelae of hepatic failure.— Van derKloot, W. Inhibition of packing of acetylcholine into quanta by ammonium.FASEB J.1: 298‐302; 1987.

ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.3498657

出版商:Wiley    

年代:1987

数据来源: WILEY

摘要:

The net glucuronidation of bilirubin (BR) has been determined in inbred and outbred rat strains and their subpopulations with similar glucuronosyltransferase (EC 2.4.1.17) activity but with different levels of β‐glucuronidase (βG) (EC 3.2.1.31), or in which the level of βG activity was reduced withd‐glucaro‐1,4‐lactone. These studies demonstrated that outbred rat strains consist of two subpopulations that differ approximately 1.5‐ to twofold in serum and liver βG activity. Evidence is presented indicating that owing to its compartmentalization the lysosomal βG, unlike the corresponding microsomal enzyme, is neither inhibited by glucarolactone nor accessible for hydrolysis of newly synthesized glucuronides. The ratio of glucuronidated to unconjugated BR 15 min after injection of albumin‐bound BR into the tail vein appears to correlate negatively with the liver microsomal βG activity. The results may be relevant to the relative risk to toxins, including carcinogens, and to their reduction by dietary intervention.—Dwivedi, C.; Downie, A. A.; Webb, T. E. Net glucuronidation in different rat strains: importance of microsomal β‐glucuronidase.FASEB J.1: 303‐307; 1987.

ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.3115856

出版商:Wiley    

年代:1987

数据来源: WILEY

摘要:

Twenty‐one isolated, perfused, spontaneously rhythmic guinea pig hearts (Langendorff preparation) were used to investigate the effects of coronary perfusion pressure (CPP) on the coronary vasoactive response to a continuous infusion of histamine. Heart rate (HR), coronary perfusate flow (CPF), left ventricular pressure, dp/dtmax, oxygen extraction, and myocardial oxygen consumption (MV˙O2) were measured at constant CPP of 40 (n= 9), 53 (n= 6), and 65 cm H2O (n= 6) in the absence and presence of continuous intracoronary infusion of histamine [0.9 ± 0.2 μg/(min · g)]. At 40 cm H2O histamine caused significant coronary vasodilation. At 65 cm H2O histamine caused significant coronary vasoconstriction. At an intermediate pressure of 53 cm H2O histamine had no effect on CPF. At all three pressures HR, left ventricular pressure, dp/dtmax, and oxygen extraction increased significantly in response to histamine.MV˙O2was unchanged by histamine at 65 cm H2O (flow was reduced but extraction increased).MV˙O2, increased modestly but significantly at 53 cm H2O (12% increase; flow unchanged but extraction increased), and increased prominently at 40 cm H2O (50% increase; flow and extraction increased). We conclude that the coronary vascular effects of continuously infused histamine are dependent on the preexisting, steady‐state level of CPP in the isolated perfused guinea pig heart.— Merrill, G. F.; Kang, Y. H.; Wei, H. M.; Fisher, H. Pressure‐dependent vasoactive effects of histamine in the coronary circulation.FASEB J.1: 308‐311; 1987.

ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.3653582

出版商:Wiley    

年代:1987

数据来源: WILEY

摘要:

Type β transforming growth factor (TGF‐β) is found in large amounts in bone tissue, and is a potent mitogen for osteoblast‐enriched cell cultures obtained from fetal rat parietal bone. Because other local and systemic factors may be presented to bone cells simultaneously with TGF‐β, it is important to understand the effects of this complex growth regulator in such circumstances. Unlike the effects observed in many tissue systems, TGF‐β does not invariably inhibit the mitogenic response of bone cells to other growth promoters. In contrast, other factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and type α tumor necrosis factor (TNF‐α) limit the response of osteoblastic bone cells to TGF‐β. TGF‐β is a much weaker mitogen for fibroblastic cells obtained from fetal rat bone, whereas fetal bovine serum, EGF, bFGF, and TNF‐α are more potent stimulators. In addition, TGF‐β does not significantly impair the response of the fibroblastic bone cells to the other tested agents. These findings reinforce a role of TGF‐β as an anabolic bone growth regulator, and suggest that its function may be modified by other local or systemic agents that can also affect bone cells.—Centrella, M.; McCarthy, T. L.; Canalis, E. Mitogenesis in fetal rat bone cells simultaneously exposed to type β transforming growth factor and other growth regulators.FASEB J.1: 312‐317; 1987.

ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.3498658

出版商:Wiley    

年代:1987

数据来源: WILEY

摘要:

We report here studies of the synthesis of lyso(bis)‐phosphatidic acid [L(b)PA] by normal and BCG‐elicited rabbit alveolar macrophages. This study was prompted by our earlier observations that1) alveolar macrophages did not synthesize L(b)PA de novo despite its abundance in these cells,2) BCG‐elicited cells contained only one‐quarter the amount of L(b)PA as normal cells, and3) the turnover of arachidonate in L(b)PA led to hydroxyeicosatetraenoic acid and leukotriene synthesis. We found that exogenous phosphatidylglycerol (PG) was specifically converted to L(b)PA by both types of cells although BCG‐elicited cells had only one‐quarter the synthetic capacity of normal cells. Other phospholipids were found to become cell associated but were not significantly metabolized. Both glycerol moieties and the phosphate were incorporated into the product L(b)PA. However, substitution of the ester with an alkyl linkage in position 1 blocked the conversion of PG to L(b)PA. Most of the alkylphosphatidylglycerol was converted to phosphatidylcholine and phosphatidylethanolamine. This result implied that catabolism of the acyl group in position 1 was essential for L(b)PA synthesis. Because alveolar macrophages are present in a surfactant‐rich milieu, we suggest that surfactant provides a source of PG for macrophage synthesis of L(b)PA in situ. It is interesting that the surfactants from rabbits challenged with BCG have a significant decrease in PG content.—Waite, M.; Roddick, V.; Thornburg, T; King, L.; Cochran, F. Conversion of phosphatidylglycerol to lyso(bis)phosphatidic acid by alveolar macrophages.FASEB J.1: 318‐325; 1987.

ISSN:0892-6638    

DOI:10.1096/fasebj.1.4.3653583

出版商:Wiley    

年代:1987

数据来源: WILEY