Key molecules in the GABA signalling pathway are present in mouse and human cervical tissue

2018 ◽  
Vol 30 (9) ◽  
pp. 1267
Author(s):  
Marta Skelin ◽  
Danijel Bursać ◽  
Viviana Kozina ◽  
Tristan Winters ◽  
Marija Macan ◽  
...  
Keyword(s):  
Superficial Layer ◽  
Signalling Pathway ◽  
Mucus Secretion ◽  
Secretory Cells ◽  
Acid Decarboxylase ◽  
Gamma Aminobutyric Acid ◽  
Cervical Tissue ◽  
Secretory Epithelium ◽  
Mrna Transcripts ◽  
Glutamic Acid Decarboxylase 65

Cervical mucus modulates fertility by cyclical changes of its biophysical and functional properties. Based on an analogy with bronchial goblet cells we set out to investigate the possible role of the gamma-aminobutyric acid (GABA) signalling pathway in the mediation of oestrogen-induced mucus secretion from endocervical secretory cells. The aim of the study was to examine the existence of GABAA receptor (GABAAR), glutamic acid decarboxylase 65/67 (GAD65/67) and vesicular GABA transporter (VGAT) in human and mouse cervical tissue. The mouse cervical tissue expressed GabaAR mRNA transcripts throughout the oestrous cycle. GABAAR-positive immunolabelling was present in the superficial layer of the mouse cervico–vaginal epithelium in pro-oestrus. Human cervical tissue showed the presence of GABAAR, GAD67 and VGAT mRNA transcripts and clear immunofluorescent signals of all three molecules were detected in the endocervical secretory epithelium. The results of this study confirmed that elements of the GABA signalling pathway are present in the secretory epithelium of mouse and human cervical tissue and that GABA signalling pathway could be considered a possible mediator in oestrogen regulation of mucus secretion in the endocervical glands.

Screening for MOG-IgG and 27 other anti-glial and anti-neuronal autoantibodies in ‘pattern II multiple sclerosis’ and brain biopsy findings in a MOG-IgG-positive case

2016 ◽  
Vol 22 (12) ◽  
pp. 1541-1549 ◽  
Author(s):  
Sven Jarius ◽  
Imke Metz ◽  
Fatima Barbara König ◽  
Klemens Ruprecht ◽  
Markus Reindl ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Brain Biopsy ◽  
Acid Decarboxylase ◽  
Gamma Aminobutyric Acid ◽  
Serum Samples ◽  
Metabotropic Glutamate ◽  
Histopathological Studies

Background: Histopathological studies have revealed four different immunopathological patterns of lesion pathology in early multiple sclerosis (MS). Pattern II MS is characterised by immunoglobulin and complement deposition in addition to T-cell and macrophage infiltration and is more likely to respond to plasma exchange therapy, suggesting a contribution of autoantibodies. Objective: To assess the frequency of anti-myelin oligodendrocyte glycoprotein (MOG), anti-M1-aquaporin-4 (AQP4), anti-M23-AQP4, anti-N-methyl-d-aspartate-type glutamate receptors (NMDAR) and 25 other anti-neural antibodies in pattern II MS. Methods: Thirty-nine serum samples from patients with MS who had undergone brain biopsy ( n = 24; including 13 from patients with pattern II MS) and from histopathologically non-classified MS patients ( n = 15) were tested for anti-MOG, anti-M1-AQP4, anti-M23-AQP4, anti-NMDAR, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-type glutamate receptors (AMPAR), anti-gamma-aminobutyric acid receptors (GABABR), anti-leucine-rich, glioma-activated protein 1 (LGI1), anti-contactin-associated protein 2 (CASPR2), anti-dipeptidyl-peptidase-like protein-6 (DPPX), anti-Tr/Delta/notch-like epidermal growth factor–related receptor (DNER), anti-Hu, anti-Yo, anti-Ri, anti-Ma1/Ma2, anti-CV2/collapsin response mediator protein 5 (CRMP5), anti-glutamic acid decarboxylase (GAD), anti-amphiphysin, anti-Ca/RhoGTPase-activating protein 26 (ARHGAP26), anti-Sj/inositol-1,4,5-trisphosphate receptor 1 (ITPR1), anti-Homer3, anti-carbonic anhydrase–related protein (CARPVIII), anti-protein kinase gamma (PKCgamma), anti-glutamate receptor delta 2 (GluRdelta2), anti-metabotropic glutamate receptor 1 (mGluR1) and anti-mGluR5, as well as for anti-glial nuclei antibodies (AGNA) and Purkinje cell antibody 2 (PCA2). Results: Antibodies to MOG belonging to the complement-activating immunoglobulin G1 (IgG1) subclass were detected in a patient with pattern II MS. Detailed brain biopsy findings are shown. Conclusion: This is the largest study on established anti-neural antibodies performed in MS so far. MOG-IgG may play a role in a small percentage of patients diagnosed with pattern II MS.

GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus

2003 ◽  
Vol 90 (4) ◽  
pp. 2690-2701 ◽  
Author(s):  
Kimmo Jensen ◽  
Chi-Sung Chiu ◽  
Irina Sokolova ◽  
Henry A. Lester ◽  
Istvan Mody
Keyword(s):  
Gaba Release ◽  
Gabab Receptors ◽  
Acid Decarboxylase ◽  
Wild Type ◽  
Gaba Transporter ◽  
Inhibitory Neurotransmitter ◽  
Gaba Transporters ◽  
Gaba Transporter 1 ◽  
Glutamic Acid Decarboxylase 65 ◽  
Deficient Mice

After its release from interneurons in the CNS, the major inhibitory neurotransmitter GABA is taken up by GABA transporters (GATs). The predominant neuronal GABA transporter GAT1 is localized in GABAergic axons and nerve terminals, where it is thought to influence GABAergic synaptic transmission, but the details of this regulation are unclear. To address this issue, we have generated a strain of GAT1-deficient mice. We observed a large increase in a tonic postsynaptic hippocampal GABAA receptor-mediated conductance. There was little or no change in the waveform or amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) or miniature IPSCs. In contrast, the frequency of quantal GABA release was one-third of wild type (WT), although the densities of GABAA receptors, GABAB receptors, glutamic acid decarboxylase 65 kDa, and vesicular GAT were unaltered. The GAT1-deficient mice lacked a presynaptic GABAB receptor tone, present in WT mice, which reduces the frequency of spontaneous IPSCs. We conclude that GAT1 deficiency leads to enhanced extracellular GABA levels resulting in an overactivation of GABAA receptors responsible for a postsynaptic tonic conductance. Chronically elevated GABA levels also downregulate phasic GABA release and reduce presynaptic signaling via GABAB receptors thus causing an enhanced tonic and a diminished phasic inhibition.

scholarly journals Similarities Between Bacterial GAD and Human GAD65: Implications in Gut Mediated Autoimmune Type 1 Diabetes

2021 ◽  
Author(s):  
Monica Westley ◽  
Tiffany Richardson ◽  
Suhana Bedi ◽  
Baofeng Jia ◽  
Fiona S.L. Brinkman ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Gut Microbiome ◽  
Pancreatic Beta Cells ◽  
Acid Decarboxylase ◽  
Host Immune System ◽  
Gamma Aminobutyric Acid ◽  
Human Gut ◽  
Autoimmune Attack

Abstract    A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD65 and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing silico analyses, we show here that 25 GAD sequences from different human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that a majority of gut GAD sequences contain the pyroxical dependent decarboxylase domain of human GAD65 which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T-cell receptor epitopes which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities, we found between humans and bacterial GAD, these deputized immune cells may then go on to target human beta cells leading to the development of T1D.

scholarly journals Exercise training modulates glutamic acid decarboxylase-65/67 expression through TrkB signaling to ameliorate neuropathic pain in rats with spinal cord injury

2020 ◽  
Vol 16 ◽  
pp. 174480692092451
Author(s):  
Xiangzhe Li ◽  
Qinghua Wang ◽  
Jie Ding ◽  
Sheng Wang ◽  
Chuanming Dong ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neuropathic Pain ◽  
Exercise Training ◽  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
Acid Decarboxylase ◽  
Cord Injury ◽  
Tropomyosin Related Kinase B ◽  
Glutamic Acid Decarboxylase 65

Neuropathic pain is one of the most frequently stated complications after spinal cord injury. In post-spinal cord injury, the decrease of gamma aminobutyric acid synthesis within the distal spinal cord is one of the main causes of neuropathic pain. The predominant research question of this study was whether exercise training may promote the expression of glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67, which are key enzymes of gamma aminobutyric acid synthesis, within the distal spinal cord through tropomyosin-related kinase B signaling, as its synthesis assists to relieve neuropathic pain after spinal cord injury. Animal experiment was conducted, and all rats were allocated into five groups: Sham group, SCI/PBS group, SCI-TT/PBS group, SCI/tropomyosin-related kinase B-IgG group, and SCI-TT/tropomyosin-related kinase B-IgG group, and then T10 contusion SCI model was performed as well as the tropomyosin-related kinase B-IgG was used to block the tropomyosin-related kinase B activation. Mechanical withdrawal thresholds and thermal withdrawal latencies were used for assessing pain-related behaviors. Western blot analysis was used to detect the expression of brain-derived neurotrophic factor, tropomyosin-related kinase B, CREB, p-REB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord. Immunohistochemistry was used to analyze the distribution of CREB, p-CREB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord dorsal horn. The results showed that exercise training could significantly mitigate the mechanical allodynia and thermal hyperalgesia in post-spinal cord injury and increase the synthesis of brain-derived neurotrophic factor, tropomyosin-related kinase B, CREB, p-CREB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord. After the tropomyosin-related kinase B signaling was blocked, the analgesic effect of exercise training was inhibited, and in the SCI-TT/tropomyosin-related kinase B-IgG group, the synthesis of CREB, p-CREB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord were also significantly reduced compared with the SCI-TT/PBS group. This study shows that exercise training may increase the glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 expression within the spinal cord dorsal horn through the tropomyosin-related kinase B signaling, and this mechanism may play a vital role in relieving the neuropathic pain of rats caused by incomplete SCI.

scholarly journals Islet cell and glutamic acid decarboxylase-65 autoantibodies in young diabetic patients attending in a General Hospital in Dhaka City

2020 ◽  
Vol 46 (2) ◽  
pp. 104-108
Author(s):  
Ashesh Kumar Chowdhury ◽  
Shahjalalur Rahman Sahi ◽  
Mohammad Moniruzzaman ◽  
Mansura Khan
Keyword(s):  
Beta Cell ◽  
Diabetic Control ◽  
Acid Decarboxylase ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Significant Difference ◽  
Gad 65 ◽  
Glutamic Acid Decarboxylase 65 ◽  
Type 2 Diabetic

Background: Immune mediated destruction of pancreatic beta cell in type-I diabetes is well established but its’ role in young type-2 diabetic patients is still not conclusive. These young diabetic patients pass through several stages where they do not need insulin but found to have serum autoantibody against islets cell and even become dependent on insulin for survival in course of time. This study aims to find the presence of islets cell auto-antibodies (ICA) and autoantibody to glutamic acid decarboxylase-65 (GAD-65) in non-insulin requiring young diabetic patients of Bangladesh. Objective: To evaluate the presence of ICA and GAD-65 between the non-insulin requiring young type-2 diabetic patients and compare with the non-diabetic control group. Method: This case control study was carried out at the Department of Immunology, BIRDEM General Hospital, Dhaka for a period of one year from July 2013, A total of 120 non-insulin requiring (≥12 months) young type-2 diabetic patients and 60 age, sex matched non-diabetic were enrolled as control subjects following inclusion and exclusion criteria. ICA and GAD-65 tests were performed by enzyme linked immune-sorbent assay (ELISA) method by using kits from DRG Inc. International, USA. Results: In this study statistically significant difference found between non insulin requiring young diabetic patients and non diabetic control in respect of positive ICA result (p=0.015). The moderately strong negative association was found between different age of onset of diabetes mellitus and value of ICA level (r=-0.45). Only 20-24 years age group showed statistically significant difference between patient and control (p=0.013). Statistically significant difference was not found in GAD-65 values of non insulin requiring young diabetic patients and non diabetic controls (p=0.441). Conclusion: This study revealed that there is significant difference present in respect of ICA among non-insulin requiring young diabetic patients and non-diabetic controls. Therefore, autoimmune pathogenesis of beta cell killing by producing ICA against islets cell take place in young type-2 diabetic patients. Bangladesh Med Res Counc Bull 2020; 46(2): 104-108

scholarly journals Neurological Syndromes Associated with Anti-GAD Antibodies

2020 ◽  
Vol 21 (10) ◽  
pp. 3701 ◽  
Author(s):  
Maëlle Dade ◽  
Giulia Berzero ◽  
Cristina Izquierdo ◽  
Marine Giry ◽  
Marion Benazra ◽  
...  
Keyword(s):  
Unmet Need ◽  
Acid Decarboxylase ◽  
Gamma Aminobutyric Acid ◽  
Gad Antibodies ◽  
Intracellular Enzyme ◽  
Inhibitory Neurotransmitter ◽  
Predictors Of Response ◽  
Physiologic Function ◽  
The Central Nervous System ◽  
Relative Rarity

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.

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