Isoproterenol-induced beta-2 adrenergic receptor activation negatively regulates interleukin-2 signaling

2018 ◽  
Vol 475 (18) ◽  
pp. 2907-2923 ◽  
Author(s):  
Blanca E. Ruiz-Medina ◽  
Denisse A. Cadena-Medina ◽  
Edmundo Esparza ◽  
Amy J. Arrieta ◽  
Robert A. Kirken
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Adrenergic Receptor ◽  
Interleukin 2 ◽  
Chain Complex ◽  
Receptor Activation ◽  
Effector Proteins ◽  
Cell Trafficking ◽  
Gamma Chain ◽  
Human Lymphoid Cell

Regulation of intracellular signaling pathways in lymphocytes is critical for cell homeostasis and immune response. Interleukin-2 (IL-2), a key regulator of lymphocytes, signals following receptor-ligand engagement and subsequent recruitment and activation of effector proteins including JAKs and STATs. Lymphocytes can also be regulated by the central nervous system through the β2 adrenergic receptor (β2AR) pathway which can affect cell trafficking, proliferation, differentiation, and cytokine production. The cross-talk between these two signaling pathways represents an important mechanism that has yet to be fully elucidated. The present study provides evidence for communication between the IL-2 receptor (IL-2R) and β2AR. Treatment of human lymphoid cell lines with the β2AR agonist isoproterenol (ISO) alone increased cAMP levels and mediated a stimulatory response by activating AKT and ERK to promote cell viability. Interestingly, ISO activation of β2AR also induced threonine phosphorylation of the IL-2Rβ. In contrast, ISO treatment prior to IL-2 stimulation produced an inhibitory signal that disrupted IL-2 induced activation of the JAK/STAT, MEK/ERK, and PI3K pathways by inhibiting the formation of the IL-2R beta–gamma chain complex, and subsequently cell proliferation. Moreover, γc-family cytokines-mediated STAT5 activation was also inhibited by ISO. These results suggest a molecular mechanism by which β2AR signaling can both stimulate and suppress lymphocyte responses and thus explain how certain therapeutic agents, such as vasodilators, may impact immune responsiveness.

scholarly journals BDNF-endocannabinoid interactions at neocortical inhibitory synapses require phospholipase C signaling

2014 ◽  
Vol 111 (5) ◽  
pp. 1008-1015 ◽  
Author(s):  
Liangfang Zhao ◽  
Eric S. Levine
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Metabotropic Glutamate Receptor ◽  
Glutamate Release ◽  
Brain Slices ◽  
Receptor Activation ◽  
Inhibitory Synapses ◽  
Trkb Receptor ◽  
Layer 2

Endogenous cannabinoids (endocannabinoids) and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), are potent synaptic modulators that are expressed throughout the forebrain and play critical roles in many behavioral processes. Although the effects of BDNF at excitatory synapses have been well characterized, the mechanisms of action of BDNF at inhibitory synapses are not well understood. Previously we have found that BDNF suppresses presynaptic GABA release in layer 2/3 of the neocortex via postsynaptic tropomyosin-related kinase receptor B (trkB) receptor-induced release of endocannabinoids. To examine the intracellular signaling pathways that underlie this effect, we used pharmacological approaches and whole cell patch-clamp techniques in layer 2/3 pyramidal neurons of somatosensory cortex in brain slices from juvenile Swiss CD1 mice. Our results indicated that phospholipase Cγ (PLCγ) is involved in the CB1 receptor-mediated synaptic effect of BDNF, because the BDNF effect was blocked in the presence of the broad-spectrum PLC inhibitors U-73122 and edelfosine, whereas the inactive analog U-73343 did not alter the suppressive effect of BDNF at inhibitory synapses. Endocannabinoid release can also be triggered by metabotropic glutamate receptor (mGluR)-mediated activation of PLCβ, and BDNF has been shown to enhance spontaneous glutamate release. An mGluR antagonist, E4CPG, however, did not block the BDNF effect. In addition, the effect of BDNF was independent of other signaling pathways downstream of trkB receptor activation, namely, mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, as well as protein kinase C signaling.

scholarly journals Structural Insights into CB1 Receptor Biased Signaling

2019 ◽  
Vol 20 (8) ◽  
pp. 1837 ◽  
Author(s):  
Al-Zoubi ◽  
Morales ◽  
Reggio
Keyword(s):  
Signaling Pathways ◽  
Conformational Changes ◽  
Intracellular Signaling ◽  
Cannabinoid Receptors ◽  
Computational Modelling ◽  
Structural Features ◽  
Cb1 Receptor ◽  
Effector Proteins ◽  
Spectroscopic Techniques ◽  
Receptor Ligands

The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) or the immune system (CB2), among other organs and tissues. CB1 receptor ligands have been shown to induce a complex pattern of intracellular effects. The binding of a ligand induces distinct conformational changes in the receptor, which will eventually translate into distinct intracellular signaling pathways through coupling to specific intracellular effector proteins. These proteins can mediate receptor desensitization, trafficking, or signaling. Ligand specificity and selectivity, complex cellular components, and the concomitant expression of other proteins (which either regulate the CB1 receptor or are regulated by the CB1 receptor) will affect the therapeutic outcome of its targeting. With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques (such as NMR, EPR, MS, FRET, and X-ray crystallography), as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation. This review will focus on the structural features of the CB1 receptor, mutations known to bias its signaling, and reported studies of CB1 receptor ligands to control its specific signaling.

scholarly journals PDGF and intracellular signaling in the timing of oligodendrocyte differentiation.

1989 ◽  
Vol 109 (6) ◽  
pp. 3411-3417 ◽  
Author(s):  
I K Hart ◽  
W D Richardson ◽  
S R Bolsover ◽  
M C Raff
Keyword(s):  
Signaling Pathways ◽  
Progenitor Cells ◽  
Intracellular Signaling ◽  
Progenitor Cell ◽  
Receptor Activation ◽  
Oligodendrocyte Differentiation ◽  
Intracellular Signaling Pathways ◽  
Parsimonious Explanation ◽  
Oligodendrocyte Development

In the rat optic nerve, bipotential O-2A progenitor cells give rise to oligodendrocytes and type 2 astrocytes on a precise schedule. Previous studies suggest that PDGF plays an important part in timing oligodendrocyte development by stimulating O-2A progenitor cells to proliferate until they become mitotically unresponsive to PDGF, stop dividing, and differentiate automatically into oligodendrocytes. Since the loss of mitotic responsiveness to PDGF has been shown not to be due to a loss of PDGF receptors, we have now examined the possibility that the unresponsiveness results from an uncoupling of these receptors from early intracellular signaling pathways. We show that (a) although PDGF does not stimulate newly formed oligodendrocytes to synthesize DNA, it induces an increase in cytosolic Ca2+ in these cells; (b) a combination of a Ca2+ ionophore plus a phorbol ester mimics the effect of PDGF, both in stimulating O-2A progenitor cell division and in reconstituting the normal timing of oligodendrocyte differentiation in culture; and (c) the same combination of drugs does not stimulate newly formed oligodendrocytes to proliferate, even in the presence of PDGF or dibutyryl cAMP. The most parsimonious explanation for these results is that O-2A progenitor cells become mitotically unresponsive to PDGF because the intracellular signaling pathways from the PDGF receptor to the nucleus are blocked downstream from the receptor and some of the early events that are triggered by receptor activation.

scholarly journals MLC1: A New Calcium-regulated Protein Conferring Calcium Dependence to Volume-regulated Anion Channels (VRAC) in Astrocytes.

2022 ◽  
Author(s):  
Maria Stefania Brignone ◽  
Angela Lanciotti ◽  
Antonio Michelucci ◽  
Cinzia Mallozzi ◽  
Serena Camerini ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Brain Edema ◽  
Intracellular Signaling ◽  
Regulatory Volume Decrease ◽  
Physiological Role ◽  
Anion Channel ◽  
Effector Proteins ◽  
Astrocyte Swelling ◽  
Cultured Astrocytes ◽  
Intracellular Ca

Abstract MLC1 is a membrane protein highly expressed by brain perivascular astrocytes. Mutations in the MLC1 gene account for megalencephalic leukoencephalopathy with subcortical cysts (MLC), an incurable leukodystrophy characterized by macrocephaly, brain edema and cysts, myelin vacuolation and astrocyte swelling, causing cognitive and motor dysfunctions. It has been demonstrated that MLC1 mutations affect the swelling-activated Cl - currents (I Cl,swell ) mediated by volume-regulated anion channel (VRAC) and the consequent regulatory volume decrease (RVD) and lead to abnormal activation of intracellular signaling pathways linked to inflammation/osmotic stress. Despite this knowledge, the MLC1 physiological role and MLC molecular pathogenesis are still elusive. Following the observations that Ca 2+ regulates all the MLC1-modulated processes and that intracellular Ca 2+ homeostasis is altered in MLC1-defective cells, we applied a multidisciplinary approach including biochemistry, molecular biology, video imaging, electrophysiology and proteomic techniques on cultured astrocytes to uncover new Ca 2+ -dependent signaling pathways controlling MLC1 function. Here, we revealed that MLC1 binds the Ca 2+ effector proteins calmodulin (CaM) and Ca 2+ /CaM-dependent protein kinase II (CaMKII) and, as result, changes its assembly, localization and functional properties in response to Ca 2+ changes. Noteworthy, CaM binding to the COOH terminal promotes MLC1 trafficking to the plasma membrane, while CaMKII phosphorylation of the NH 2 -terminal potentiates MLC1 activation of I Cl,swell . Overall, these results revealed that MLC1 is a Ca 2+ -regulated protein linking VRAC function and, possibly, volume regulation to Ca 2+ signaling in astrocytes. These findings open new avenues of investigations aimed at clarifying the abnormal molecular pathways underlying MLC and other diseases characterized by astrocyte swelling and brain edema.

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