Abstract
Control of GABA neurotransmission at the pre-synaptic site occurs substantially through the activation of the glutamic acid decarboxylase (GAD) enzymes GAD65 and GAD67. Concentrations of GAD65 and GAD67 are controlled either by transcription or by mRNA splicing and importantly the activities of these key enzymes are regulated by post-translational mechanisms. Important post-translational modifications include proteolytic cleavage, phosphorylation and palmitoylation. A truncated form of GAD65 (tGAD65) is more active than full length GAD65 (fGAD65) whereas, by contrast, truncated GAD67 (tGAD67) is less active than full length GAD67 (fGAD67). The protein responsible for cleaving of fGAD65 and fGAD67 is mu-calpain. GABA neurotransmission is dependent upon whether GAD is associated with synaptic vesicles (SV) and calpain performs a vital role by generating the highly active tGAD65 resulting in augmented GABA synthesis and wrapping uptake into SV. Studies on GAD phosphorylation demonstrate that GAD65 is regulated through phosphorylation by PKC while GAD67 is inhibited through phosphorylation by PKA. Cysteine residues 455 and 446 in GAD67 and GAD65 individually are critical for full GAD regulation. Interaction with the cofactor pyridoxal 50-phosphate (PLP) at this these respective locations regulate the switch between PLP-bound active holoGAD and an unbound active apoGAD form. Transient switching to the PLP bound active holoGAD is integral to GABA neurotransmission. Specific to GAD65 but not GAD67 is palmitoylation by HIP14 which facilitates GAD65 anchoring to SV and enhances the contribution of vesicular GABA to neurotransmission. From studies on a rodent stroke model calpain-mediated cleavage of GAD enzyme has been shown to occur under pathological conditions resulting in less SV refilling and depletion of existing pools of SV releasable GABA.
Keywords: Glutamic acid decarboxylase, calpain, GABA neurotransmission, vesicular GABA release, palmitoylation, phosphorylation.
Current Pharmaceutical Design
Title:Regulation of GABA Neurotransmission by Glutamic Acid Decarboxylase (GAD)
Volume: 21 Issue: 34
Author(s): Jigar Pravinchandra Modi, Howard Prentice and Jang-Yen Wu
Affiliation:
Keywords: Glutamic acid decarboxylase, calpain, GABA neurotransmission, vesicular GABA release, palmitoylation, phosphorylation.
Abstract: Control of GABA neurotransmission at the pre-synaptic site occurs substantially through the activation of the glutamic acid decarboxylase (GAD) enzymes GAD65 and GAD67. Concentrations of GAD65 and GAD67 are controlled either by transcription or by mRNA splicing and importantly the activities of these key enzymes are regulated by post-translational mechanisms. Important post-translational modifications include proteolytic cleavage, phosphorylation and palmitoylation. A truncated form of GAD65 (tGAD65) is more active than full length GAD65 (fGAD65) whereas, by contrast, truncated GAD67 (tGAD67) is less active than full length GAD67 (fGAD67). The protein responsible for cleaving of fGAD65 and fGAD67 is mu-calpain. GABA neurotransmission is dependent upon whether GAD is associated with synaptic vesicles (SV) and calpain performs a vital role by generating the highly active tGAD65 resulting in augmented GABA synthesis and wrapping uptake into SV. Studies on GAD phosphorylation demonstrate that GAD65 is regulated through phosphorylation by PKC while GAD67 is inhibited through phosphorylation by PKA. Cysteine residues 455 and 446 in GAD67 and GAD65 individually are critical for full GAD regulation. Interaction with the cofactor pyridoxal 50-phosphate (PLP) at this these respective locations regulate the switch between PLP-bound active holoGAD and an unbound active apoGAD form. Transient switching to the PLP bound active holoGAD is integral to GABA neurotransmission. Specific to GAD65 but not GAD67 is palmitoylation by HIP14 which facilitates GAD65 anchoring to SV and enhances the contribution of vesicular GABA to neurotransmission. From studies on a rodent stroke model calpain-mediated cleavage of GAD enzyme has been shown to occur under pathological conditions resulting in less SV refilling and depletion of existing pools of SV releasable GABA.
Export Options
About this article
Cite this article as:
Modi Pravinchandra Jigar, Prentice Howard and Wu Jang-Yen, Regulation of GABA Neurotransmission by Glutamic Acid Decarboxylase (GAD), Current Pharmaceutical Design 2015; 21 (34) . https://dx.doi.org/10.2174/1381612821666150917094343
DOI https://dx.doi.org/10.2174/1381612821666150917094343 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Oxidative Stress in the Early Stage of Psychosis
Current Topics in Medicinal Chemistry Organotypic Cultures as Tool to Test Long-Term Effects of Chemicals on the Nervous System
Current Medicinal Chemistry Natural Triterpenoids and their Derivatives with Pharmacological Activity Against Neurodegenerative Disorders
Mini-Reviews in Organic Chemistry The Proteasome in Health and Disease
Current Pharmaceutical Design Post-Translational Protein Modifications of Rare and Unconventional Types: Implications in Functions and Diseases
Current Medicinal Chemistry Molecular Pharmacology of the Glycine Receptor Chloride Channel
Current Pharmaceutical Design Tyrosine Kinases as New Molecular Targets in Treatment of Inflammatory Disorders and Leukemia
Current Pharmaceutical Design The Flavin-Containing Monoooxygenases (FMOs): Genetic Variation and its Consequences for the Metabolism of Therapeutic Drugs
Current Pharmacogenomics The Co-Metabolism within the Gut-Brain Metabolic Interaction: Potential Targets for Drug Treatment and Design
CNS & Neurological Disorders - Drug Targets Ontologies of Drug Discovery and Design for Neurology, Cardiology and Oncology
Current Pharmaceutical Design Kinase Inhibitors as Potential Therapeutics for Acute and Chronic Neurodegenerative Conditions
Current Pharmaceutical Design Targeting the Alpha 7 Nicotinic Acetylcholine Receptor to Reduce Amyloid Accumulation in Alzheimers Disease Pyramidal Neurons
Current Pharmaceutical Design Pathophysiological Role of Mitochondrial Potassium Channels and their Modulation by Drugs
Current Medicinal Chemistry Liposomes as siRNA Delivery Vectors
Current Drug Metabolism Nanotechnology-based Targeting of Neurodegenerative Disorders: A Promising Tool for Efficient Delivery of Neuromedicines
Current Drug Targets Patent Selections
Recent Patents on Cardiovascular Drug Discovery Low Molecular Weight Compounds with Transition Metals as Free Radical Scavengers and Novel Therapeutic Agents
Cardiovascular & Hematological Agents in Medicinal Chemistry Development of Neurotrophic Molecules for Treatment of Neurode-generation
Current Protein & Peptide Science Prion Protein Misfolding
Current Molecular Medicine Life and Death of Nerve Cells: Therapeutic Cytokine Signaling Pathways
Current Signal Transduction Therapy