scholarly journals Forebrain-Specific Inactivation of Gq/G11 Family G Proteins Results in Age-Dependent Epilepsy and Impaired Endocannabinoid Formation

2006 ◽  
Vol 26 (15) ◽  
pp. 5888-5894 ◽  
Author(s):  
Nina Wettschureck ◽  
Mario van der Stelt ◽  
Hiroshi Tsubokawa ◽  
Heinz Krestel ◽  
Alexandra Moers ◽  
...  
Keyword(s):  
G Proteins ◽  
Neuronal Excitability ◽  
Metabotropic Receptors ◽  
Cannabinoid Type 1 Receptor ◽  
Age Dependent ◽  
Α Subunits ◽  
Increased Susceptibility

ABSTRACT Metabotropic receptors coupled to Gq/G11 family G proteins critically contribute to nervous system functions by modulating synaptic transmission, often facilitating excitation. We investigated the role of Gq/G11 family G proteins in the regulation of neuronal excitability in mice that selectively lack the α-subunits of Gq and G11, Gαq and Gα11, respectively, in forebrain principal neurons. Surprisingly, mutant mice exhibited increased seizure susceptibility, and the activation of neuroprotective mechanisms was impaired. We found that endocannabinoid levels were reduced under both basal and excitotoxic conditions and that increased susceptibility to kainic acid could be normalized by the enhancement of endocannabinoid levels with an endocannabinoid reuptake inhibitor, while the competitive cannabinoid type 1 receptor antagonist SR141716A did not cause further aggravation. These findings indicate that Gq/G11 family G proteins negatively regulate neuronal excitability in vivo and suggest that impaired endocannabinoid formation in the absence of Gq/G11 contributes to this phenotype.

scholarly journals The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 959 ◽  
Author(s):  
Jefferson Antônio Leite ◽  
Gabriela Pessenda ◽  
Isabel C. Guerra-Gomes ◽  
Alynne Karen Mendonça de Santana ◽  
Camila André Pereira ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Bacterial Translocation ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Dna Sensor ◽  
Proinflammatory Response

Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2−/−) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2−/− mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2−/− mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.

Toward heterogeneity in feedforward network with synaptic delays based on FitzHugh–Nagumo model

2018 ◽  
Vol 32 (01) ◽  
pp. 1750274 ◽  
Author(s):  
Ying-Mei Qin ◽  
Cong Men ◽  
Jia Zhao ◽  
Chun-Xiao Han ◽  
Yan-Qiu Che
Keyword(s):  
Neuronal Excitability ◽  
Temporal Coding ◽  
Feedforward Network ◽  
Firing Patterns ◽  
In Vivo Experiments ◽  
Connection Probability ◽  
Rate Coding

We focus on the role of heterogeneity on the propagation of firing patterns in feedforward network (FFN). Effects of heterogeneities both in parameters of neuronal excitability and synaptic delays are investigated systematically. Neuronal heterogeneity is found to modulate firing rates and spiking regularity by changing the excitability of the network. Synaptic delays are strongly related with desynchronized and synchronized firing patterns of the FFN, which indicate that synaptic delays may play a significant role in bridging rate coding and temporal coding. Furthermore, quasi-coherence resonance (quasi-CR) phenomenon is observed in the parameter domain of connection probability and delay-heterogeneity. All these phenomena above enable a detailed characterization of neuronal heterogeneity in FFN, which may play an indispensable role in reproducing the important properties of in vivo experiments.

scholarly journals ER stress and development of type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 2-6 ◽  
Author(s):  
Feyza Engin
Keyword(s):  
Type 1 Diabetes ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Adaptive Responses ◽  
Β Cell ◽  
Cellular Homeostasis ◽  
Unfolded Protein

Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β cells. The incidence of T1D is on the rise globally around 3% to 5% per year and rapidly increasing incidence in younger children is of the greatest concern. currently, there is no way to cure or prevent T1D; hence, a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new effective therapies. The endoplasmic reticulum (ER) is an organelle with multiple functions that are essential for cellular homeostasis. Excessive demand on the ER, chronic inflammation, and environmental factors lead to ER stress and to re-establish cellular homeostasis, the adaptive unfolded protein response (UPR) is triggered. However, chronic ER stress leads to a switch from a prosurvival to a proapoptotic UPR, resulting in cell death. Accumulating data have implicated ER stress and defective UPR in the pathogenesis of inflammatory and autoimmune diseases, and ER stress has been implicated in β-cell failure in type 2 diabetes. However, the role of ER stress and the UPR in β-cell pathophysiology and in the initiation and propagation of the autoimmune responses in T1D remains undefined. This review will highlight the current understanding and recent in vivo data on the role of ER stress and adaptive responses in T1D pathogenesis and the potential therapeutic aspect of enhancing β-cell ER function and restoring UPR defects as novel clinical strategies against this disease.

Glial Cells and Pro-inflammatory Cytokines as Shared Neurobiological Bases for Chronic Pain and Psychiatric Disorders

2020 ◽  
pp. 27-49
Author(s):  
Judith A. Strong ◽  
Sang Won Jeon ◽  
Jun-Ming Zhang ◽  
Yong-Ku Kim
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Psychiatric Disorders ◽  
Inflammatory Cytokines ◽  
Glial Cells ◽  
Neuronal Excitability ◽  
Pro Inflammatory Cytokines

This chapter reviews the roles of cytokines and glial cells in chronic pain and in psychiatric disorders, especially depression. One important role of cytokines is in communicating between activated glia and neurons, at all levels of the nervous system. This process of neuroinflammation plays important roles in pain and depression. Cytokines may also directly regulate neuronal excitability. Many cytokines have been implicated in both pain and psychiatric disorders, including interleukin-1β‎ (IL-1β‎), tumor necrosis factor-α‎, and IL-6. More generally, an imbalance between type 1, pro-inflammatory cytokines and type 2, anti-inflammatory cytokines has been implicated in both pain and psychiatric disorders. Activation of the sympathetic nervous system can contribute to both pain and psychiatric disorders, in part through its actions on inflammation and the cytokine profile.

Exposure to environmental chemicals and type 1 diabetes: an update

2019 ◽  
Vol 73 (6) ◽  
pp. 483-488 ◽  
Author(s):  
Sarah G Howard
Keyword(s):  
Type 1 Diabetes ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Environmental Chemicals ◽  
Exposure Level ◽  
Environmental Chemical ◽  
Timing Of Exposure

This narrative review summarises recently published epidemiological and in vivo experimental studies on exposure to environmental chemicals and their potential role in the development of type 1 diabetes mellitus (T1DM). These studies focus on a variety of environmental chemical exposures, including to air pollution, arsenic, some persistent organic pollutants, pesticides, bisphenol A and phthalates. Of the 15 epidemiological studies identified, 14 include measurements of exposures during childhood, 2 include prenatal exposures and 1 includes adults over age 21. Together, they illustrate that the role of chemicals in T1DM may be complex and may depend on a variety of factors, such as exposure level, timing of exposure, nutritional status and chemical metabolism. While the evidence that these exposures may increase the risk of T1DM is still preliminary, it is critical to investigate this possibility further as a means of preventing T1DM.

scholarly journals Absent in melanoma 2 inflammasome is required for host defence against Streptococcus pneumoniae infection

2019 ◽  
Vol 25 (7) ◽  
pp. 412-419 ◽  
Author(s):  
Siwei Feng ◽  
Tingting Chen ◽  
Guihua Lei ◽  
Fengqing Hou ◽  
Jiali Jiang ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pneumococcal Infection ◽  
Host Defence ◽  
Mortality And Morbidity ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Increased Susceptibility

Streptococcus pneumoniae, a leading cause of invasive pneumococcal disease, is responsible for high mortality and morbidity worldwide. A previous study showed that the NLR family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes are essential for caspase-1 activation and IL-1β production in the host response to S. pneumoniae infection. The function of NLRP3 in host innate immunity to S. pneumoniae was studied in vivo and in vitro. However, the role of AIM2 in host defence against S. pneumoniae remains unclear. Here, we show that AIM2-deficient (AIM2–/–) mice display increased susceptibility to intra-nasal infection with S. pneumoniae in comparison to wild type mice and that this susceptibility was associated with defective IL-1β production. Macrophages from AIM2–/– mice infected with S. pneumoniae showed impaired secretion of IL-1β as well as activation of the inflammasome, as determined by the oligomerisation of apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 activation. Taken together, these results indicate that the AIM2 inflammasome is essential for caspase-1-dependent cytokine IL-1β production and eventual protection from pneumococcal infection in mice.

Role of genetic variation in the cannabinoid type 1 receptor gene (CNR1) in the pathophysiology of human obesity

2010 ◽  
Vol 11 (5) ◽  
pp. 693-702 ◽  
Author(s):  
Dorit Schleinitz ◽  
Solveig Carmienke ◽  
Yvonne Böttcher ◽  
Anke Tönjes ◽  
Janin Berndt ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Receptor Gene ◽  
Human Obesity ◽  
Cannabinoid Type 1 Receptor

scholarly journals Phospholipase D in Phytophthora infestans and Its Role in Zoospore Encystment

2002 ◽  
Vol 15 (9) ◽  
pp. 939-946 ◽  
Author(s):  
Maita Latijnhouwers ◽  
Teun Munnik ◽  
Francine Govers
Keyword(s):  
Phytophthora Infestans ◽  
G Proteins ◽  
Phospholipase D ◽  
Kinase Activity ◽  
Mechanical Agitation ◽  
Protein Activator ◽  
Late Blight Pathogen ◽  
Stimulation Of

We show that differentiation of zoospores of the late blight pathogen Phytophthora infestans into cysts, a process called encystment, was triggered by both phosphatidic acid (PA) and the G-protein activator mastoparan. Mastoparan induced the accumulation of PA, indicating that encystment by mastoparan most likely acts through PA. Likewise, mechanical agitation of zoospores, which often is used to induce synchronized encystment, resulted in increased levels of PA. The levels of diacylglycerolpyrophosphate (DGPP), the phosphorylation product of PA, increased simultaneously. Also in cysts, sporangiospores, and mycelium, mastoparan induced increases in the levels of PA and DGPP. Using an in vivo assay for phospholipase D (PLD) activity, it was shown that the mastoparan-induced increase in PA was due to a stimulation of the activity of this enzyme. Phospholipase C in combination with diacylglycerol (DAG) kinase activity also can generate PA, but activation of these enzymes by mastoparan was not detected under conditions selected to highlight 32P-PA production via DAG kinase. Primary and secondary butanol, which, like mastoparan, have been reported to activate G-proteins, also stimulated PLD activity, whereas the inactive tertiary isomer did not. Similarly, encystment was induced by n- and sec-butanol but not by tert-butanol. Together, these results show that Phytophthora infestans contains a mastoparan- and bu-tanol-inducible PLD pathway and strongly indicate that PLD is involved in zoospore encystment. The role of G-proteins in this process is discussed.

scholarly journals Role of SODD in Regulation of Tumor Necrosis Factor Responses

2003 ◽  
Vol 23 (11) ◽  
pp. 4026-4033 ◽  
Author(s):  
Hidetoshi Takada ◽  
Nien-Jung Chen ◽  
Christine Mirtsos ◽  
Shinobu Suzuki ◽  
Nobutaka Suzuki ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Signaling Proteins ◽  
Ligand Stimulation ◽  
Cytotoxic Responses ◽  
Necrosis Factor

ABSTRACT Signaling from tumor necrosis factor receptor type 1 (TNFR1) can elicit potent inflammatory and cytotoxic responses that need to be properly regulated. It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation. In this study, we demonstrate that mice lacking SODD produce larger amounts of cytokines in response to in vivo TNF challenge. SODD-deficient macrophages and embryonic fibroblasts also show altered responses to TNF. TNF-induced activation of NF-κB is accelerated in SODD-deficient cells, but TNF-induced c-Jun N-terminal kinase activity is slightly repressed. Interestingly, the apoptotic arm of TNF signaling is not hyperresponsive in the SODD-deficient cells. Together, these results suggest that SODD is critical for the regulation of TNF signaling.

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