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Aplysillin A, a thrombin receptor antagonist from the marine sponge, Aplysina fistularis fulva
Title
Aplysillin A, a thrombin receptor antagonist from the marine sponge, Aplysina fistularis fulva.
Creator
Gulavita, N. K., Pomponi, Shirley A., Wright, Amy E., Garay, M., Sills, Matthew A.
Date Issued
1995
PURL
http://purl.flvc.org/FCLA/DT/3319084
Subject Headings
Sponges --Research, Marine natural products, Receptors, Thrombin, Aplysillin A, Antagonists, Enzyme, Marine pharmacology
Format
Document (PDF)
Cleavage of brain glutamic acid decarboxylase 65 by calpain under pathological conditions
Title
Cleavage of brain glutamic acid decarboxylase 65 by calpain under pathological conditions.
Creator
Buddhala, Chandana, Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
Brain glutamic acid decarboxylase 65 (GAD65) catalyzes the rate-limiting step in the biosynthesis of the major inhibitory neurotransmitter-amino butyric acid (GABA) from the substrate L-glutamic acid. Severe lapse in GABA neurotransmission is one of the etiologies documented in the manifestation of certain neurodegenerative diseases such as epilepsy, Parkinson's disease, Huntington's disease etc. Because GAD65 synthesizes GABA, any modulation of GAD65, therefore, has direct implications on...
Show moreBrain glutamic acid decarboxylase 65 (GAD65) catalyzes the rate-limiting step in the biosynthesis of the major inhibitory neurotransmitter-amino butyric acid (GABA) from the substrate L-glutamic acid. Severe lapse in GABA neurotransmission is one of the etiologies documented in the manifestation of certain neurodegenerative diseases such as epilepsy, Parkinson's disease, Huntington's disease etc. Because GAD65 synthesizes GABA, any modulation of GAD65, therefore, has direct implications on the quanta of GABA released at the synapse. Hence, the major objective of this study was to focus on the regulation of GAD65, with special emphasis on investigating the proteolytic cleavage of fGAD65. Previously, we have shown in vitro that GAD65 was cleaved to form its truncated form (tGAD65), which was more active than the full length form (fGAD65). The enzyme responsible for cleavage was later identified as calpain. Calpain is known to cleave its substrates either under a transient physiologica l stimulus or upon a sustained pathological insult. However, the precise role of calpain cleavage of fGAD65 is poorly understood. In this study, we examined the cleavage of fGAD65 under a range of conditions encompassing both physiological and pathological aspects, including rats under ischemia/reperfusion insult, rat brain synaptosomes or primary neuronal cultures subjected to excitotoxic stimulation with KCl. It was observed that the formation of tGAD65 progressively increased with increasing stimulus concentration. More importantly, cleavage of synaptic vesicle (SV) - associated fGAD65 by calpain was demonstrated, and the resulting tGAD65 harboring the active site of the enzyme was detached from the SVs. Vesicular uptake of the newly synthesized GABA into the SVs was found to be reduced in calpain treated SVs. Furthermore, we also observed that the levels of tGAD65 in the focal cerebral ischemic rat brain tissue increased corresponding to the elevation of local glutamate indica, d by in vivo micro dialysis. Based on these observations, we conclude that calpain cleavage of fGAD65 occurs under pathological conditions.
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Date Issued
2012
PURL
http://purl.flvc.org/FAU/3342053
Subject Headings
Glutamic acids, Antagonists, Proteolytic enzymes, Research, Cellular signal transduction, Calpain, Glutamic acid, Metabolism
Format
Document (PDF)
Mutant huntingtin reduces palmitoylation of GAD65 and impairs its vesicular trafficking
Title
Mutant huntingtin reduces palmitoylation of GAD65 and impairs its vesicular trafficking.
Creator
Rush, Daniel., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
Huntington's disease (HD) is caused by an expanded plyglutamine repeat in the huntingtin protein. In this study, I focused on the effect of the mutant huntingtin protein (mhtt) on the subcellular localization of glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing gama-aminobutyric acid (GABA). Subcellular distribution of GAD65 is significantly altered in two neuronal cell lines that express either the N-terminus or full length mhtt. GAD65 is predominantly associated...
Show moreHuntington's disease (HD) is caused by an expanded plyglutamine repeat in the huntingtin protein. In this study, I focused on the effect of the mutant huntingtin protein (mhtt) on the subcellular localization of glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing gama-aminobutyric acid (GABA). Subcellular distribution of GAD65 is significantly altered in two neuronal cell lines that express either the N-terminus or full length mhtt. GAD65 is predominantly associated with the Golgi membrane in cells expressing normal huntingtin (Htt). However, it diffuses in the cytosol of cells expressing mhtt. Palmitoylation of GAD65 is required for GAD65 trafficking, and I demonstrated the palmitoylation of GAD65 is reduced in the HD model. Overexpression of huntingtin-interacting protein 14 (HIP14), the enzyme that palmitoylates GAD65, rescues GAD65 palmitoylation and vesicle-associated trafficking. This data suggests that impairment of GAD65 palmitoylation by mhtt may alter its localization and lead to altered inhibitory neurotransmission in HD.
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Date Issued
2012
PURL
http://purl.flvc.org/FAU/3352831
Subject Headings
Glutamic acids, Antagonists, Cellular signal transduction, Proteolytic enzymes, Research, Proteins, Physiological transport, Huntington's chorea, Research
Format
Document (PDF)
Reciprocal regulation between taurine and glutamate response via Ca2+ - dependent pathways in retinal third-order neurons
Title
Reciprocal regulation between taurine and glutamate response via Ca2+ - dependent pathways in retinal third-order neurons.
Creator
Bulley, Simon, Shen, Wen
Date Issued
2010-08-24
PURL
http://purl.flvc.org/fcla/dt/3327274
Subject Headings
Amacrine Cells*/cytology, Amacrine Cells*/drug effects, Amacrine Cells*/metabolism, Ambystoma, Calcium/metabolism, Calcium Channels/metabolism, Cells, Cultured, Enzyme Inhibitors/metabolism, Excitatory Amino Acid Agonists/pharmacology, GABA Antagonists/pharmacology, Glutamic Acid/metabolism, Glycine Agents/pharmacology, Kainic Acid/pharmacology, Membrane Glycoproteins, Membrane Potentials, Neurotransmitter Agents, Retinal Ganglion Cells, Signal Transduction, Synaptic Transmission
Format
Document (PDF)