scholarly journals Two distinct mechanisms target GAD67 to vesicular pathways and presynaptic clusters

2010 ◽  
Vol 190 (5) ◽  
pp. 911-925 ◽  
Author(s):  
Jamil Kanaani ◽  
Julia Kolibachuk ◽  
Hugo Martinez ◽  
Steinunn Baekkeskov
Keyword(s):  
Neuroendocrine Cells ◽  
Acid Decarboxylase ◽  
Inhibitory Neurotransmitter ◽  
Golgi Membranes ◽  
The Central Nervous System ◽  
Hydrophobic Lipid ◽  
Rapid Modulation ◽  
Axonal Targeting ◽  
Membrane Anchoring ◽  
Constitutively Active

The inhibitory neurotransmitter γ-amino butyric acid (GABA) is synthesized by two isoforms of the enzyme glutamic acid decarboxylase (GAD): GAD65 and GAD67. Whereas GAD67 is constitutively active and produces >90% of GABA in the central nervous system, GAD65 is transiently activated and augments GABA levels for rapid modulation of inhibitory neurotransmission. Hydrophobic lipid modifications of the GAD65 protein target it to Golgi membranes and synaptic vesicles in neuroendocrine cells. In contrast, the GAD67 protein remains hydrophilic but has been shown to acquire membrane association by heterodimerization with GAD65. Here, we identify a second mechanism that mediates robust membrane anchoring, axonal targeting, and presynaptic clustering of GAD67 but that is independent of GAD65. This mechanism is abolished by a leucine-103 to proline mutation that changes the conformation of the N-terminal domain but does not affect the GAD65-dependent membrane anchoring of GAD67. Thus two distinct mechanisms target the constitutively active GAD67 to presynaptic clusters to facilitate accumulation of GABA for rapid delivery into synapses.

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.

scholarly journals A combination of three distinct trafficking signals mediates axonal targeting and presynaptic clustering of GAD65

2002 ◽  
Vol 158 (7) ◽  
pp. 1229-1238 ◽  
Author(s):  
Jamil Kanaani ◽  
Alaa El-Din El-Husseini ◽  
Andrea Aguilera-Moreno ◽  
Julia M. Diacovo ◽  
David S. Bredt ◽  
...  
Keyword(s):  
Aminobutyric Acid ◽  
Membrane Microdomains ◽  
Cholesterol Levels ◽  
Golgi Membranes ◽  
Selective Targeting ◽  
Localization Signal ◽  
Axonal Targeting ◽  
Membrane Anchoring ◽  
Axonal Trafficking ◽  
Axonal Sorting

The signals involved in axonal trafficking and presynaptic clustering are poorly defined. Here we show that targeting of the γ-aminobutyric acid–synthesizing enzyme glutamate decarboxylase 65 (GAD65) to presynaptic clusters is mediated by its palmitoylated 60-aa NH2-terminal domain and that this region can target other soluble proteins and their associated partners to presynaptic termini. A Golgi localization signal in aa 1–23 followed by a membrane anchoring signal upstream of the palmitoylation motif are required for this process and mediate targeting of GAD65 to the cytosolic leaflet of Golgi membranes, an obligatory first step in axonal sorting. Palmitoylation of a third trafficking signal downstream of the membrane anchoring signal is not required for Golgi targeting. However, palmitoylation of cysteines 30 and 45 is critical for post-Golgi trafficking of GAD65 to presynaptic sites and for its relative dendritic exclusion. Reduction of cellular cholesterol levels resulted in the inhibition of presynaptic clustering of palmitoylated GAD65, suggesting that the selective targeting of the protein to presynaptic termini is dependent on sorting to cholesterol-rich membrane microdomains. The palmitoylated NH2-terminal region of GAD65 is the first identified protein region that can target other proteins to presynaptic clusters.

Heterogeneity and Proliferative and Differential Regulators of NG2-glia in Physiological and Pathological States

2020 ◽  
Vol 27 (37) ◽  
pp. 6384-6406 ◽  
Author(s):  
Zuo Zhang ◽  
Hongli Zhou ◽  
Jiyin Zhou
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Physiological State ◽  
Critical Role ◽  
Adult Brain ◽  
Pathological State ◽  
Peripheral Neurons ◽  
Neuronal Synapses ◽  
The Central Nervous System ◽  
Rapid Modulation

NG2-glia, also called Oligodendrocyte Precursor Cells (OPCs), account for approximately 5%-10% of the cells in the developing and adult brain and constitute the fifth major cell population in the central nervous system. NG2-glia express receptors and ion channels involved in rapid modulation of neuronal activities and signaling with neuronal synapses, which have functional significance in both physiological and pathological states. NG2-glia participate in quick signaling with peripheral neurons via direct synaptic touches in the developing and mature central nervous system. These distinctive glia perform the unique function of proliferating and differentiating into oligodendrocytes in the early developing brain, which is critical for axon myelin formation. In response to injury, NG2-glia can proliferate, migrate to the lesions, and differentiate into oligodendrocytes to form new myelin sheaths, which wrap around damaged axons and result in functional recovery. The capacity of NG2-glia to regulate their behavior and dynamics in response to neuronal activity and disease indicate their critical role in myelin preservation and remodeling in the physiological state and in repair in the pathological state. In this review, we provide a detailed summary of the characteristics of NG2-glia, including their heterogeneity, the regulators of their proliferation, and the modulators of their differentiation into oligodendrocytes.

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.

Multiple, prolonged actions of neuroendocrine bag cells on neurons in Aplysia. I. Effects on bursting pacemaker neurons

1979 ◽  
Vol 42 (4) ◽  
pp. 1165-1184 ◽  
Author(s):  
E. Mayeri ◽  
P. Brownell ◽  
W. D. Branton ◽  
S. B. Simon
Keyword(s):  
Spike Activity ◽  
Ganglion Cells ◽  
Cell Activity ◽  
Egg Laying ◽  
Neuroendocrine Cells ◽  
Abdominal Ganglion ◽  
Normal Expression ◽  
The Central Nervous System ◽  
Bag Cells ◽  
Local Stimulation

1. The bag cells are a group of neuroendocrine cells located in the abdominal ganglion of Aplysia. Accumulated evidence suggests they synthesize and release egg-laying hormone (ELH), a peptide that induces egg laying. In this and the following paper (37) we describe five types of prolonged neural responses in cells of the isolated abdominal ganglion that are produced by stimulated bag cell activity. 2. Prolonged, 5- to 40-min bursts of spike activity were triggered in the normally silent bag cells by local stimulation of one of the bag cell clusters with brief, 0.6- to 2-strains of pulses. This local stimulation minimized the possible effects of the stimulus on other ganglion cells and initiated bag cell activity similar to what has been recorded in intact animals at the initiation of egg laying. 3. Following onset of triggered bag cell activity there is an increase in the amplitude of the bursting pacemaker potential in cell R15 that results in augmented bursting activity in this autoactive cell for up to 3 h. The increase begins in less than 1 min and reaches a maximim after 8--20 min. In two other bursting pacemaker cells, L3 and L6, there is a second type of response, slow inhibition, consisting of a smoothly graded hyperpolarization that begins in 5--14 s, reaches a peak value of 10--20 mV after 30 s, and results in a decrease in the spontaneous spike activity of these cells for 3 h or longer. Both types of responses are contingent on the occurrence of bag cell activity, they depend on prolonged bag cell activity for their normal expression, and they occur in the absence of the fast interactions characteristic of conventional synapses. 4. The results reveal at the level of intracellular recordings prolonged actions of peptide-secreting neuroendocrine cells on the central nervous system. The role of ELH as a putative mediator of one or more of these actions is discussed.

scholarly journals Organization of GABA-Containing Neurons in Some Extrapyramidal Nuclei

1980 ◽  
Vol 7 (3) ◽  
pp. 251-252 ◽  
Author(s):  
H.C. Fibiger
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
Current Knowledge ◽  
Gabaergic Neurons ◽  
Acid Decarboxylase ◽  
Extrapyramidal System ◽  
The Central Nervous System ◽  
The Subject

SUMMARY:Nuclei of the extrapyramidal system contain among the highest levels of GABA and its synthesizing enzyme glutamic acid decarboxylase (GA D) in the central nervous system. In recent years the anatomical organization of GABAergic neurons in the extrapyramidal system has been the subject of considerable experimental enquiry. In this note, current knowledge concerning the origin and projections of GABAergic neurons in certain extrapyramidal nuclei is briefly reviewed.

scholarly journals Immunocytochemical localization of aromatic L-amino acid decarboxylase in human, rat, and mouse bronchopulmonary and gastrointestinal endocrine cells.

1988 ◽  
Vol 36 (9) ◽  
pp. 1181-1186 ◽  
Author(s):  
J M Lauweryns ◽  
L Van Ranst
Keyword(s):  
Amino Acid ◽  
Aromatic Amino Acids ◽  
Nerve Fibers ◽  
Neuroendocrine Cells ◽  
Adrenergic Nerve ◽  
Acid Decarboxylase ◽  
Immunoperoxidase Method ◽  
Amino Acid Decarboxylase ◽  
Additional Tool ◽  
Mouse Tissues

Aromatic L-amino acid decarboxylase (AADC) catalyzes the cellular decarboxylation of L-aromatic amino acids and is therefore involved in the synthesis of several biogenic amines. Application of the indirect immunoperoxidase method on human, rat, and mouse tissues using specific antibodies to AADC revealed all AADC-containing cells. Besides mast cells and adrenergic nerve fibers, the following cells were immunostained: neuroendocrine cells in the tracheobronchial epithelium; neuroepithelial bodies in the bronchopulmonary epithelium; Kultschitzky cells in the small intestine and appendix as well as adrenal chromaffin cells. All the latter cells belong to the so-called APUD system, the "D" in the acronym standing for the activity of the enzyme aromatic L-amino acid decarboxylase. Immunocytochemistry for AADC may become an additional tool not only to highlight APUD cells in tissue sections but also to differentiate the sites of cellular amine synthesis from those of amine storage.

scholarly journals The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer.

1993 ◽  
Vol 178 (6) ◽  
pp. 2219-2223 ◽  
Author(s):  
P De Camilli ◽  
A Thomas ◽  
R Cofiell ◽  
F Folli ◽  
B Lichte ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Synaptic Vesicles ◽  
The Body ◽  
Acid Decarboxylase ◽  
Gad Autoantibodies ◽  
Cytoplasmic Surface ◽  
Cytoplasmic Proteins ◽  
Cns Autoimmunity ◽  
The Central Nervous System ◽  
Stiff Man Syndrome

Stiff-Man syndrome (SMS) is a rare disease of the central nervous system (CNS) characterized by progressive rigidity of the body musculature with superimposed painful spasms. An autoimmune origin of the disease has been proposed. In a caseload of more than 100 SMS patients, 60% were found positive for autoantibodies directed against the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). Few patients, all women affected by breast cancer, were negative for GAD autoantibodies but positive for autoantibodies directed against a 128-kD synaptic protein. We report here that this antigen is amphiphysin. GAD and amphiphysin are nonintrinsic membrane proteins that are concentrated in nerve terminals, where a pool of both proteins is associated with the cytoplasmic surface of synaptic vesicles. GAD and amphiphysin are the only two known targets of CNS autoimmunity with this distribution. This finding suggests a possible link between autoimmunity directed against cytoplasmic proteins associated with synaptic vesicles and SMS.

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