ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.3044902

出版商:Wiley    

年代:1988

数据来源: WILEY

摘要:

Reversible protein phosphorylation is widely recognized as an important mechanism for the regulation of cell function by a variety of physiological stimuli. Exposure of cells to hormones, neurotransmitters, and growth factors initiates a cascade of events facilitated by intracellular second messengers and mediated in many cases by protein kinases and/or phosphatases. The subsequent covalent modification of target proteins and the associated changes in their function account for the physiological response. Considerable evidence points to crosstalk between multiple membrane‐associated signaling processes leading to coordinated regulation of cellular processes. The role of protein phosphorylation at multiple points in the pathways that integrate these signals is becoming increasingly apparent. Pharmacological modulation of cellular protein phosphorylation has yielded useful information on the molecular events involved. This review surveys some of the recent progress in hormonal regulation of cell function, focusing on examples that may provide new insight into the role of protein phosphorylation in the coordinated control of cellular processes by physiological stimuli.—Shenolikar, S. Protein phosphorylation: hormones, drugs, and bioregulation.FASEB J.2: 2753‐2764; 1988.

ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.2842213

出版商:Wiley    

年代:1988

数据来源: WILEY

摘要:

The hormone melatonin is secreted primarily from the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone, through an action in the brain, appears to be involved in the regulation of various neural and endocrine processes that are cued by the daily change in photoperiod. This article reviews the pharmacological characteristics and function of melatonin receptors in the central nervous system, and the role of melatonin in mediating physiological functions in mammals. Melatonin and melatonin agonists, at picomolar concentrations, inhibit the release of dopamine from retina through activation of a site that is pharmacologically different from a serotonin receptor. These inhibitory effects are antagonized by the novel melatonin receptor antagonist luzindole (N‐0774), which suggests that melatonin activates a presynaptic melatonin receptoir. In chicken and rabbit retina, the pharmacological characteristics of the presynaptic melatonin receptor and the site labeled by 2‐[125I]iodomelatonin are identical. It is proposed that 2‐[125I]iodomelatonin binding sites (e.g., chicken brain) that possess the pharmacological characteristics of the retinal melatonin receptor site (order of affinities: 2‐iodomelatonin>6‐chloromelatonin ≥ melatonin ≥ 6,7‐di‐chloro‐2‐methylmelatonin>6‐hydroxymelatonin ≥ 6‐methoxymelatonin>N‐acetyltryptamine ≥ luzindole>N‐acetyl‐5‐hydroxytryptamine>5‐methoxytryptamine>>>>5‐hydroxytryptamine) be classified as ML‐1 (melatonin 1). The 2‐[125I]iodomelatonin binding site of hamster brain membranes possesses different binding and pharmacological characteristics from the retinal melatonin receptor site and should be classified as ML‐2. In summary, the recent advances in the pharmacological characterization of melatonin receptors in the central nervous system will further stimulate the search for potent and selective melatonin receptor agonists and antagonists, and should aid in our understanding of the mechanism of action of melatonin in mammalian brain.— Dubocovigh, M. L. Pharmacology and function of melatonin receptors.FASEB J.2: 2765‐2773; 1988.

ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.2842214

出版商:Wiley    

年代:1988

数据来源: WILEY

摘要:

Heme biosynthesis in hepatocytes is controlled by a free heme pool, which regulates δ‐aminolevulinic acid synthase. Porphyrinogenic chemicals deplete the regulatory free heme pool by interacting with cytochrome P‐450 thereby inhibiting heme biosynthesis and/or causing heme breakdown. Recent developments allow us to predict which groups of chemicals are likely to be porphyrinogenic. One group is exemplified by 3,5‐diethoxycarbonyl‐1,4‐dihydro‐2,4,6‐trimethylpyridine. Heterocyclic compounds of this type cause mechanism‐based inactivation of cytochrome P‐450, leading to the formation of N‐alkylporphyrins, with ferrochelatase‐inhibitory activity resulting in lowering the free heme pool. Allylisopropylacetamide exemplifies a second group. Such compounds containing a terminal olefinic or acetylenic group, cause mechanism‐based inactivation of cytochrome P‐450. In the process, the heme moiety of cytochrome P‐450 is destroyed and the free heme pool is lowered. A third group is exemplified by planar polyhalogenated or polycyclic aromatic hydrocarbons. These compounds induce specific cytochrome P‐450 isozymes but are poor substrates. Active oxygen is formed, which interacts with a hepatic substrate to form a uroporphyrinogen decarboxylase inhibitor. Inhibition of this enzyme leads to depletion of the free heme pool.—Marks, G. S.; McCluskey, S. A.; Mackie, J. E.; Riddick, D. S.; James, C. A. Disruption of hepatic heme biosynthesis after interaction of xenobiotics with cytochrome P‐450.FASEB J.2: 2774‐2783; 1988.

ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.3044903

出版商:Wiley    

年代:1988

数据来源: WILEY

摘要:

G proteins act as transducers between membrane receptors activated by extracellular signals and enzymatic effectors controlling the concentration of cytosolic signal molecules such as cAMP, cGMP, inositol phosphates and Ca2+. In some instances, the receptor/G protein‐induced changes in the concentration of cytosolic signal molecules correlate with activity changes of voltage‐dependent Ca2+channels. Ca2+channel modulation, in these cases, requires the participation of protein kinases whose activity is stimulated by cytosolic signal molecules. The respective protein kinases phosphorylate Ca2+channel‐forming proteins or unknown regulatory components. More recent findings suggest another membrane‐confined mechanism that does not involve cytosolic signal molecules but rather a more direct control of voltage‐dependent Ca2+channels by G proteins. Modulation of Ca2+channel activity that follows this apparently membrane‐confined mechanism has been described to occur in neuronal, cardiac, and endocrine cells. The G protein involved in the hormonal stimulation of Ca2+channels in endocrine cells may belong to the family of Gi‐type G proteins, which are functionally uncoupled from activating receptors by pertussis toxin. The G protein G3, which is activated by cholera toxin, may stimulate cardiac Ca2+channels without the involvement of a cAMP‐dependent intermediate step. Hormonal inhibition of Ca2+channels in neuronal and endocrine cells is mediated by a pertussis toxin‐sensitive G protein, possibly G∗∗∗o. Whether G proteins act by binding directly to Ca2+channels or through interaction with as yet undetermined regulatory components of the plasma membrane remains to be clarified.— Rosenthal, W.; Hescheler, J.; Trautwein, W.; Schultz, G. Control of voltage‐dependent Ca2+channels by G protein‐coupled receptors.FASEB J.2: 2784‐2790; 1988.

ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.2457531

出版商:Wiley    

年代:1988

数据来源: WILEY

摘要:

Multidrug resistance (MDR) refers to a complex phenotype that describes a number of features characterized primarily by resistance to a wide range of structurally unrelated drugs. In this paper we investigated the relationship between drug resistance and resistance to NK‐mediated cytotoxicity. Studies with two independently selected multidrug‐resistant cell lines indicated that increased drug resistance was associated with both an increased resistance to NK‐mediated cytotoxicity and increased levels of membrane P‐glycoprotein expression. This resistance to cytotoxicity appears to result partly from an alteration in the membrane structure of the target cells inasmuch as there was a reduction in effector:target cell recognition. Resistance to NK‐mediated cytotoxicity should be included with the numerous pleiotropic changes associated with the multidrug resistance phenotype.—Woods, G.; Lund, L. A.; Naik, M.; Ling, V.; Ochi, A. Resistance of multidrug‐resistant lines to natural killer‐like cell mediated cytotoxicity.FASEB J.2: 2791‐2796; 1988.

ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.3044904

出版商:Wiley    

年代:1988

数据来源: WILEY

摘要:

Heparin‐binding growth factors (HBGF) are essential and key mitogens for human adult large vessel endothelial cells. At 170 pg/ml, the tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) caused a 50% inhibition of heparin‐binding growth factor type one (HBGF‐1)‐stimulated DNA synthesis in human adult large vessel endothelial cells. TPA at 1 ng/ml completely inhibited HBGF‐1‐stimulated proliferation. TPA at 5 ng/ml reduced specific HBGF‐1 receptor sites from 6600 per cell to 3200 per cell without affecting receptor affinity. Since phorbol esters are potent activators of protein kinase C, these results suggest that activation of protein kinase C desensitizes both animal capillary and human adult large vessel endothelial cells to the mitogenic effects of HBGF by down‐regulation of specific HBGF receptors.— Hoshi, H.; Kan, M.; Mioh, H.; Chen, J.‐K.; McKeehan, W. L. Phorbol ester reduces number of heparin‐binding growth factor receptors in human adult endothelial cells.FASEB J.2: 2797‐2800; 1988.

ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.2457532

出版商:Wiley    

年代:1988

数据来源: WILEY

摘要:

The membrane glycoproteins CD4 (L3T4) and CD8 (Lyt2) are expressed on distinct populations of mature murine T lymphocytes, and are thought to be receptors for monomorphic determinants expressed on MHC class II and class I molecules, respectively. Although they differ in their ligand specificity, it has been presumed that CD4 and CD8 perform equivalent functions in the T cells that bear them. Since activation of protein kinase C (PKC) is known to cause rapid down‐regulation of various receptors, including the T cell receptor complex (TcR complex), we treated cells with phorbol 12‐myristate 13‐acetate (PMA), a PKC activator, to determine whether cell‐surface expression of CD4 and CD8 would be similarly affected by this intracellular mediator. Brief or relatively prolonged treatment with PMA induced mature murine T cells to reduce their surface expression of the TcR complex and of CD4, but not of CD8. Similarly, PMA rapidly induced transfected L cells to down‐regulate surface CD4 expression, but had no effect on surface CD8 expression. Most significantly, PMA treatment induced CD4+CD8+immature thymocytes to rapidly reduce their surface CD4 expression, but, again, it had no immediate effect on the surface expression of CD8. These results indicate that CD4 and TcR complex cell‐surface expression are both sensitive to PKC activation by brief treatment with PMA, whereas CD8 expression is not, and suggest that CD4 and CD8 surface expression levels are regulated by distinct intracellular mechanisms.— Kaldjian, E.; McCarthy, S. A.; Sharrow, S. O.; Littman, D. R.; Klausner, R. D.; Singer, A. Nonequivalent effects of PKS activation by PMA on murine CD4 and CD8 cell surface expression.FASEB J.2: 2801‐2806; 1988.

ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.3261700

出版商:Wiley    

年代:1988

数据来源: WILEY

摘要:

Age‐dependent changes in glucose homeostasis were assessed in specific pathogen‐free C57BL/6J male mice. Increased islet size and pancreatic insulin content in old (21‐25‐month‐old) mice were associated with lower nonfasting plasma glucose levels and improved clearance of either an oral or an i.p. administered glucose load in comparison with young, mature (4‐5‐month‐old) males. The almost twofold increase in islet size correlated with a twofold increase of glucose‐stimulated insulin secretion from perifused islets from 25‐month‐old males compared with 5‐month‐old males. These aging male mice did not become obese, and there were no fibrotic changes associated with the hyperplastic islets observed in the old males. Thus, the findings that glucose tolerance did not deteriorate with age, coupled with the lack of evidence for impairedβcell responsiveness to glucose in old males, suggest that deterioration in glucose homeostasis is not an inevitable consequence of aging in the mouse.— Leiter, E. H.; Premdas, F.; Harrison, D. E.; Lipson, L. G. Aging and glucose homeostasis in C57BL/6J male mice.FASEB J.2: 2807‐2811; 1988.

ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.3044905

出版商:Wiley    

年代:1988

数据来源: WILEY

摘要:

In the present study, we evaluated whether mononuclear leukocytes could synthesize and secrete growth hormone (GH) in vitro. By using RNA slot blot analysis, we detected maximum spontaneous levels of specific GH mRNA in the cytoplasm of rat leukocytes after a 4‐h incubation. Northern gel analysis demonstrated that the specific leukocyte GH RNA was polyadenylated and had a molecular mass of 1.0 kb. Further studies using immunofluorescence, antibody affinity chromatography, and Sephacryl gel filtration indicate that leukocytes secrete a high molecular weight (>300,000) and a low molecular weight (~ 22,000) immunoreactive GH (irGH). A substantial amount of the high molecular weight irGH can be converted to the lower molecular weight form after reduction with mercaptoethanol. The irGH appeared to be de novo synthesized because it could be radiolabeled with tritiated amino acids and its production could be blocked by previous incubation of leukocytes with cycloheximide. The replication of Nb2 rat node lymphoma cells was stimulated by affinity‐purified human lymphocyte‐derived irGH. The growth stimulation was blocked by specific antibodies to hGH. We conclude that lymphocytes produce an irGH that is similar to if not identical to pituitary GH in terms of bioactivity, antigenicity, and molecular weight. The findings demonstrate a potential regulatory loop between the immune and neuroendocrine tissues.—Weigent, D. A.; Baxter, J. B.; Wear, W. E.; Smith, L. R.; Bost, K. L.; Blalock, J. E. Production of immunoreactive growth hormone by mononuclear leukocytes.FASEB J.2: 2812‐2818; 1988.

ISSN:0892-6638    

DOI:10.1096/fasebj.2.12.3044906

出版商:Wiley    

年代:1988

数据来源: WILEY