Tissue-specific modulation of rat glucocorticoid receptor binding activity by melatonin

The effect of melatonin and 2-Iodomelatonin on nuclear and cytosolic glucocorticoid receptors in the brain, pituitary, thymus and liver has been examined. The results indicate that both melatonin and 2-Iodomelatonin administration is associated with marked changes in the density and the affinity of cytosolic and nuclear forms of glucocorticoid receptors. These observations are discussed in the context of a possible involvement of pineal melatonin in the mechanisms regulating the behaviour and metabolism of steroid receptors.     

Number of glucocorticoid receptors in lymphocytes and their sensitivity to hormone action

The study demonstrated a decreased level of glucocorticoid receptors (GR) in peripheral blood lymphocytes from hypercholesterolemic subjects, and an elevated level in patients with acute myocardial infarction. In the lymphocytes with a high GR number, dexamethasone inhibited [3H]-thymidine and [3H]-acetate incorporation into DNA and cholesterol, respectively, in the same manner as in the control cells. On the other hand, a decreased GR number resulted in a less efficient dexamethasone inhibition of the incorporation of labeled compounds. These data showed that the sensitivity of lymphocytes to glucocorticoids changed only with a decrease of GR level.     

Decreased number of asialoglycoprotein receptors in diabetic BB Wistar rat

The binding of asialoglycoproteins by hepatic binding protein was studied in freshly isolated hepatocytes from genetically diabetic BB Wistar rats. The number of cell surface asialoglycoprotein receptors was dramatically decreased (58,000 +/- 38,000 for diabetic rats compared to 267,000 +/- 70,000 for normal rats), while the association equilibrium constant was not changed. These results parallel those obtained with streptozotocin-diabetic rats and support the hypothesis that insulin deprivation is responsible for the decrease in the receptor number.     

Evidence for synergism in steroid hormone-receptor association.

A number of glucocorticoids stimulated oestradiol binding to liver cytosol receptor; oestradiol activated glucocorticoid receptor association at a time when it reversed triamcinolone mediated increase in liver glycogen synthesis.     

Decreased number of asialoglycoprotein receptors in diabetic BB Wistar rat

Summary The binding of asialoglycoproteins by hepatic binding protein was studied in freshly isolated hepatocytes from genetically diabetic BB Wistar rats. The number of cell surface asialoglycoprotein receptors was dramatically decreased (58,000±38,000 for diabetic rats compared to 267,000±70,000 for normal rats), while the association equilibrium constant was not changed. These results parallel those obtained with streptozotocin-diabetic rats and support the hypothesis that insulin deprivation is responsible for the decrease in the receptor number.     

Introduction: lipids as regulators of cell function

It is becoming increasingly clear that lipids are key regulators of cellular function and that these effects are quite diverse. First, the lipid environment in the cellular membrane bilayer is important in maintaining the normal function of receptors, enzymes, transporters and so on that are localized in the membrane. Phosphoinositides are important regulators of signalling molecules. Lipid metabolites formed by a number of enzymes including the cyclooxygenases, lipoxygenases and P450s also mediate important cellular functions. Fatty acids and lipid metabolites can also activate the nuclear peroxisome proliferator-activated receptors. Finally, a wide variety of lipid molecules are generated nonenzymatically by free-radical mechanisms that also exert potent biological effects in a wide variety of organs. Presented are a series of eight reviews that broadly cover all of these topics in some detail.     

Evidence for synergism in steroid hormone-receptor association

Summary A number of glucocorticoids stimulated oestradiol binding to liver cytosol receptor; oestradiol activated glucocorticoid receptor association at a time when it reversed triamcinolone mediated increase in liver glycogen synthesis.These studies were supported by the DRGST (IMB 7570744), the INSERM (CL 7650014) and the CNRS (AI 03 1917).     

Effect of aminoglutethimide on murine fetal hepatic erythroid colony formation

Pretreatment of pregnant mice with aminoglutethimide phosphate, an inhibitor of glucocorticoid synthesis, increases the content of fetal liver erythroid colony-forming cells (CFU-E), as assessed by the formation of erythroid colonies in vitro by fetal liver cells in plasma clots containing exogenous erythropoietin. In addition, the inability of aminoglutethimide to influence erythroid colony formation in vitro suggests that endogenous glucocorticoids exert a suppressive effect on the number of functional CFU-E in the fetal liver.     

Pituitary gonadotropin releasing hormone (GnRH) receptor levels in intact and ovariectomized-adrenalectomized female golden hamsters on a short photoperiod

Summary Both intact and ovariectomized+adrenalectomized hamsters on a short photoperiod, had a daily surge in plasma LH at approximately 16.00–18.00 h. The number of pituitary GnRH receptors was generally lower in ovariectomized+adrenalectomized hamsters than in intact animals, but both intact and ovariectomized+adrenalectomized hamsters had a decrease in the number of receptors just prior to the LH surge. These results show that gonadal steroids are not involved in regulating the pre-LH surge fall in the number of GnRH receptors.     

Pituitary gonadotropin releasing hormone (GnRH) receptor levels in intact and ovariectomized-adrenalectomized female golden hamsters on a short photoperiod

Both intact and ovariectomized + adrenalectomized hamsters on a short photoperiod, had a daily surge in plasma LH at approximately 16.00-18.00 h. The number of pituitary GnRH receptors was generally lower in ovariectomized + adrenalectomized hamsters than in intact animals, but both intact and ovariectomized + adrenalectomized hamsters had a decrease in the number of receptors just prior to the LH surge. These results show that gonadal steroids are not involved in regulating the pre-LH surge fall in the number of GnRH receptors.     

Intracellular trafficking of AMPA receptors in synaptic plasticity

Modification of ligand-gated receptor function at the postsynaptic domain is one of the most important mechanisms by which the efficacy of synaptic transmission in the nervous system is regulated. Traditionally, these types of modifications have been thought to be achieved mainly by altering the channel-gating properties or conductance of the receptors. However, recent evidence suggests that AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxayolepropionic acid)-type ligand-gated glutamate receptors are continuously recycling between the plasma membrane and the intracellular compartments via vesicle-mediated plasma membrane insertion and clathrin-dependent endocytosis. Regulation of either receptor insertion or endocytosis results in a rapid change in the number of these receptors expressed on the plasma membrane surface and in the receptor-mediated responses, thereby playing an important role in mediating certain forms of synaptic plasticity. Thus, controlling the number of postsynaptic receptors by regulating the intracellular trafficking and plasma membrane expression of the postsynaptic receptors may be a common and important mechanism of synaptic plasticity in the mammalian central nervous system.     

Interleukin 7 and thymic stromal lymphopoietin: from immunity to leukemia

Cancer is often caused by deregulation of normal developmental processes. Here, we review recent research on the aberrant activation of two hematopoietic cytokine receptors in acute lymphoid leukemias. Somatic events in the genes for thymic stromal lymphopoietin and Interleukin 7 receptors as well as in their downstream JAK kinases result in constitutive ligand-independent activation of survival and proliferation in B and T lymphoid precursors. Drugs targeting these receptors or the signaling pathways might provide effective therapies of these leukemias.     

Stress,glucocorticoid receptors,and adult neurogenesis: a balance between excitation and inhibition?

Adult neurogenesis, the birth of new neurons in the mature brain, has attracted considerable attention in the last decade. One of the earliest identified and most profound factors that affect adult neurogenesis both positively and negatively is stress. Here, we review the complex interplay between stress and adult neurogenesis. In particular, we review the role of the glucocorticoid receptor, the main mediator of the stress response in the proliferation, differentiation, migration, and functional integration of newborn neurons in the hippocampus. We review a multitude of mechanisms regulating glucocorticoid receptor activity in relationship to adult neurogenesis. We postulate a novel concept in which the level of glucocorticoid receptor expression directly regulates the excitation-inhibition balance, which is key for proper neurogenesis. We furthermore argue that an excitation-inhibition dis-balance may underlie aberrant functional integration of newborn neurons that is associated with psychiatric and paroxysmal brain disorders.     

The role of the cilium in normal and abnormal cell cycles: emphasis on renal cystic pathologies

The primary cilium protrudes from the cell surface and acts as a sensor for chemical and mechanical growth cues, with receptors for a number of growth factors (PDGFα, Hedgehog, Wnt, Notch) concentrated within the ciliary membrane. In normal tissues, the cilium assembles after cells exit mitosis and is resorbed as part of cell cycle re-entry. Although regulation of the cilium by cell cycle transitions has been appreciated for over 100 years, only recently have data emerged to indicate the cilium also exerts influence on the cell cycle. The resorption/protrusion cycle, regulated by proteins including Aurora-A, VHL, and GSK-3β, influences cell responsiveness to growth cues involving cilia-linked receptors; further, resorption liberates the ciliary basal body to differentiate into the centrosome, which performs discrete functions in S-, G2-, and M-phase. Besides these roles, the cilium provides a positional cue that regulates polarity of cell division, and thus directs cells towards fates of differentiation versus proliferation. In this review, we summarize the specific mechanisms mediating the cilia-cell cycle dialog. We then emphasize the examples of polycystic kidney disease (PKD), nephronopthisis (NPHP), and VHL-linked renal cysts as cases in which defects of ciliary function influence disease pathology, and may also condition response to treatment.     

Impaired nuclear translocation of glucocorticoid receptors: novel findings from psoriatic epidermal keratinocytes

Psoriasis is a chronic proliferative skin disease and is usually treated with topical glucocorticoids, which act through the glucocorticoid receptor (GR), a component of the physiological systems essential for immune responses, differentiation, and homeostasis. To investigate the possible role of GR in the pathogenesis of psoriasis, normal and psoriatic lesional skin were recruited. Firstly, the immunolocalization of GR in the skin and cultured epidermal keratinocytes were determined by immunofluorescence. In normal skin and cultured human epidermal keratinocytes, intracellular GR is localized in the nuclei, while in psoriatic skin and cultured keratinocytes, GR is in the cytoplasm. Next, we investigated possible factors associated with the cytoplasmic distribution. We found that VEGF and IFN-γ led to impaired nuclear translocation of GR through p53 and microtubule-inhibitor, vincristine, and inhibited nuclear uptake of GR in normal keratinocytes. In addition to dexamethasone, interleukin (IL)-13 was also able to transfer GR into nuclei of psoriatic keratinocytes. Furthermore, discontinuation of dexamethasone induced cytoplasmic retention of GR in normal keratinocytes. In contrast, energy depletion of normal epidermal keratinocytes did not change the nuclear distribution of GR. To confirm our findings in vivo, an imiquimod-induced psoriasis-like skin mouse model was included. IL-13 ameliorated (but vincristine exacerbated) the skin lesions on the mouse. Taken together, our findings define that impaired nuclear translocation of GR is associated with VEGF, IFN-γ, p53, and microtubule. Therapeutic strategies designed to accumulate GR in the nucleus, such as IL-13, may be beneficial for the therapy of psoriasis.     

Activation of type-2 cannabinoid receptor inhibits neuroprotective and antiinflammatory actions of glucocorticoid receptor α: when one is better than two

Endocannabinoids (eCBs) and glucocorticoids (GCs) are two distinct classes of signaling lipids that exert both neuroprotective and immunosuppressive effects; however, the possibility of an actual interaction of their receptors [i.e., type-2 cannabinoid (CB₂) and glucocorticoid receptor α (GRα), respectively] remains unexplored. Here, we demonstrate that the concomitant activation of CB₂ and GRα abolishes the neuroprotective effects induced by each receptor on central neurons and on glial cells in animal models of remote cell death. We also show that the ability of eCBs and GCs, used individually, to inhibit tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production from activated human T lymphocytes is lost when CB₂ and GRα are activated simultaneously. In addition, signal transduction pathways triggered by concomitant activation of both receptors led to increased levels of GRβ, heat-shock proteins-70 and -90, and p-JNK, as well as to reduced levels of p-STAT6. These effects were reversed only by selectively antagonizing CB₂, but not GRα. Overall, our study demonstrates for the first time the existence of a CB₂-driven negative cross-talk between eCB and GC signaling in both rats and humans, thus paving the way to the possible therapeutic exploitation of CB₂ as a new target for chronic inflammatory and neurodegenerative diseases.