Diversity and Functions of GABA Receptors: A Tribute to Hanns Mohler, Part B (eBook)

Uwe Rudolph (Herausgeber)

eBook Download: PDF | EPUB

2015 | 1. Auflage
284 Seiten
Elsevier Science (Verlag)
978-0-12-802691-5 (ISBN)

Infos

Diversity and Functions of GABA Receptors: A Tribute to Hanns M”hler, Part B, a new volume of Advances in Pharmacology, presents the diversity and functions of GABA Receptors. The volume looks at research performed in the past 20 years, which has revealed specific physiological and pharmacological functions of individual GABAA receptor subtypes, providing novel opportunities for drug development. - Contributions from the best authors in the field - An essential resource for pharmacologists, immunologists, and biochemists

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Diversity and Functions of GABA Receptors: A Tribute to Hanns Mohler, Part B, a new volume of Advances in Pharmacology, presents the diversity and functions of GABA Receptors. The volume looks at research performed in the past 20 years, which has revealed specific physiological and pharmacological functions of individual GABAA receptor subtypes, providing novel opportunities for drug development. - Contributions from the best authors in the field- An essential resource for pharmacologists, immunologists, and biochemists

Inhalt

Front Cover 1
Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part B 4
Copyright 5
Contents 6
Preface 10
Contributors 14
Chapter 1: Reflections on More Than 30 Years Association with Hanns 16
1. Introduction 16
2. Conclusion 24
Conflict of Interest 24
References 24
Chapter 2: Significance of GABAA Receptor Heterogeneity: Clues from Developing Neurons 28
1. Introduction 29
1.1. Early days 31
1.2. GABAA receptors and GABAergic transmission in developing CNS 33
1.3. Switch in GABAA receptor subunit composition during development 36
1.4. GABAA receptors and adult neurogenesis 42
1.5. Significance for CNS diseases 44
2. Conclusion 47
Conflict of Interest 47
Acknowledgments 47
References 47
Chapter 3: Regulation of Cell Surface GABAB Receptors: Contribution to Synaptic Plasticity in Neurological Diseases 56
1. Introduction 57
1.1. Structural organization of GABAB receptors 58
1.2. GABAB receptor effector systems 60
1.2.1. Presynaptic effector systems 61
1.2.2. Postsynaptic effector systems 61
2. Phosphorylation of GABAB Receptors 62
2.1. cAMP-dependent protein kinase 62
2.2. Protein kinase C 63
2.3. Calcium/calmodulin-dependent kinase II 63
2.4. 5'-Adenosine monophosphate-activated protein kinase 64
3. Degradation of GABAB Receptors 64
4. Contribution of Altered Cell Surface GABAB Receptor Expression to Neurological Diseases 66
4.1. Drug addiction 67
4.2. Neuropathic pain 69
4.3. Brain ischemia 71
5. Potential Therapeutic Implications 74
6. Conclusion 76
Conflict of interest 77
References 77
Chapter 4: Restoring the Spinal Pain Gate: GABAA Receptors as Targets for Novel Analgesics 86
1. Introduction 87
2. Synaptic Disinhibition in Pathological Pain 90
3. Spinal GABAAR Subtypes Mediating Antihyperalgesia: Evidence from Genetically Engineered Mice 92
4. Mechanisms of Spinal Benzodiazepine-Mediated Antihyperalgesia 95
4.1. Contribution of presynaptic inhibition and primary afferent depolarization 95
4.1.1. Mechanisms of presynaptic inhibition 97
5. Antihyperalgesic Action of Benzodiazepines with Improved Subtype Specificity: Preclinical Studies 98
5.1. Addiction 100
5.2. Tolerance development against antihyperalgesia 100
6. Clinical Studies on Antihyperalgesia by Benzodiazepines 101
7. Open Questions 102
7.1. Which GABAAR subtypes should be targeted for optimal analgesia with minimal side-effects? 102
7.2. Mixed GABAARs with more than one type of a subunit 103
8. Conclusion 104
Conflict of interest statement 104
Acknowledgment 104
References 104
Chapter 5: GABAergic Control of Depression-Related Brain States 112
1. Introduction 113
2. The GABAergic Deficit Hypothesis of MDD 115
3. GABAergic Transmission and Heritability of MDD 121
4. GABAergic Transmission in Relation to the Monoamine Deficiency Hypothesis of MDD 122
5. GABAergic Transmission in Relation to Stress-Based Etiologies of MDD 127
6. GABAergic Transmission in Relation to the Neurotrophic Deficit Hypothesis of MDD 130
7. GABAergic Transmission in Relation to Glutamatergic Etiologies of MDD 134
8. Conclusion 138
Conflict of interest 140
Acknowledgments 140
References 140
Chapter 6: Mechanisms of Fast Desensitization of GABAB Receptor-Gated Currents 160
1. Introduction 161
2. Homologous Desensitization Operating at the Receptor 163
3. Homologous Desensitization Operating at the a and ß. Subunits of the G Protein 164
3.1. RGS-induced fast desensitization 165
3.2. GRK-induced fast desensitization 168
3.3. KCTD12-induced fast desensitization 169
4. Slow and Fast Mechanisms of Desensitization Influence Each Other 171
5. Conclusion 172
Conflict of interest 173
Acknowledgments 173
References 174
Chapter 7: Allosteric Ligands and Their Binding Sites Define .-Aminobutyric Acid (GABA) Type A Receptor Subtypes 182
1. Introduction 183
1.1. .-Aminobutyric acid 183
1.2. Brief history of function/pharmacophysiology and binding of GABAA receptors 184
1.2.1. The GABA sites 186
1.2.2. The BZ sites 186
1.2.3. The picrotoxinin sites 189
1.2.4. GABAAR: Summary based on the three ligands 193
1.3. Identification of ligand binding sites and their three-dimensional location: Affinity labeling, mutagenesis, X-ray c... 193
1.3.1. Picrotoxin sites lead to discovery of the anesthetic sites 193
1.3.2. GABA and BZ sites at subunit interfaces 196
1.3.3. Benzodiazepine sites lead to discovery of the ethanol (EtOH)-sensitive benzodiazepine (BZ) sites, distinct from th... 197
1.3.4. Structure of GABAAR: Mutagenesis and affinity labeling to identify functional domains especially ligand binding si... 201
2. Conclusion 206
Conflict of interest 206
Acknowledgments 206
References 206
Chapter 8: Diversity in GABAergic Signaling 218
1. Introduction 219
2. Factors Shaping the Neuronal Transmembrane Chloride Gradient 221
2.1. Resting membrane potential 221
2.2. K-Cl cotransporter 2 221
2.3. Na-K-Cl cotransporter 1 222
2.4. Impermeable anions 223
3. Experimental Techniques to Study Chloride Homeostasis and E-GABAA 223
3.1. Classical electrophysiology 224
3.2. Imaging 224
3.2.1. Chloride-sensitive dyes 225
3.2.2. Genetically encoded chloride sensors 225
3.2.3. Voltage-sensitive dye imaging 226
4. Variability of GABAergic Signaling 226
4.1. Variability in the temporal domain 226
4.1.1. Developmental timeframe 226
4.1.2. Seasonal timeframe 228
4.1.3. Day-to-day variation and circadian rhythms 229
4.1.4. Chloride homeostasis-dependent long-term plasticity 229
4.1.5. Short-term activity- dependent chloride regulation 230
4.2. Variability in the spatial domain 230
4.2.1. Interspecies variability 230
4.2.2. Gender differences 231
4.2.3. Region-specific chloride homeostasis 231
4.2.4. Cell type-specific chloride homeostasis 231
4.2.5. Subcellular variation in chloride handling and GABAergic signaling 232
5. Conclusion 232
Conflict of interest 233
References 233
Chapter 9: The Diversity of GABAA Receptor Subunit Distribution in the Normal and Huntington´s Disease Human Brain1 238
1. Introduction 239
1.1. GABAA receptors 239
1.1.1. Basal ganglia 240
1.1.2. Neurochemical compartments 241
1.1.3. GABAARs in the human basal ganglia 243
1.1.3.1. Regional localization 243
1.2. GABAAR subunit localization 244
1.2.1. Regional distribution striatum (Fig.2) 244
1.2.2. Regional distribution globus pallidus 246
1.3. GABAA receptor subunit cellular distribution (Figs.3 and 4) 247
1.3.1. Striatum 247
1.3.1.1. Medium spiny neuron 247
1.3.1.2. Interneurons 248
1.3.2. Globus pallidus 250
1.3.3. Substantia nigra (Fig.5) 251
1.3.4. Subunit combinations 251
2. Neuropathology of the Basal Ganglia in Huntington´s Disease 256
2.1. Macroscopic changes 256
2.2. Grading of striatal neuropathology 257
3. Cellular and Neurochemical Changes 257
3.1. Striatum 257
3.2. Globus pallidus 261
3.3. Substantia nigra 262
3.4. Parkinson´s disease 265
3.5. Subventricular zone and neurogenesis in Huntington´s disease 266
3.6. Huntington´s disease-related proteins association with GABAA receptor subunits 268
3.7. Overall distribution and function of the GABAA receptor in the human basal ganglia 269
Conflict of interest 270
Acknowledgments 270
References 270
Index 280

Textauszug

Chapter One

Reflections on More Than 30 Years Association with Hanns

Norman G. Bowery1    Department of Pharmacology, University of Birmingham Medical School, Edgbaston, United Kingdom
1 Corresponding author: email address: [e-mail]

Abstract

I first met Hanns in 1977 and soon learnt of his extraordinary ability as a researcher. He became a friend as well as a mentor providing enthusiasm for my own research. I watched closely over the years how his research uncovered details of the association of the benzodiazepines and GABA and delineated the structural composition of the GABAA receptor associated with the action of individual drugs such as antianxiety and antiepileptic agents. His work produced many important contributions to medicine notable of which was the discovery of the first benzodiazepine antagonists, which are now routinely used in clinical practice. But for me his most important contribution was the discovery of the benzodiazepine receptor. During this time, my group uncovered a novel receptor for GABA and my progress in this work was encouraged and enhanced by discussions with Hanns.

Keywords

GABAB

GABAA

Benzodiazepine receptor

Baclofen

1 Introduction

It is a great honor for me to contribute to this volume in recognition of the work of one of the most, if not the most, prolific researcher in the field of benzodiazepines, Hanns Möhler. He has been foremost in the discovery of the basis for their actions and for facilitating the introduction of different benzodiazepines into clinical medicine and there is no doubt that his contribution has been of paramount importance.

I first met Hanns in Spatind, Norway, where we were attending one of the most influential symposia in the field of amino acid neurotransmission. It was organized by Frode Fonnum under the auspices of NATO. One focus of the presentations was the establishment of binding sites for GABA in mammalian brain tissue as exemplified by Enna, Beaumont, and Yamamura (1978), Lloyd and Dreksler (1978), and Olsen, Greenlee, Van Ness, and Ticku (1978). In addition, there were many “firsts” at this meeting. An example of which was the possibility that endogenous “inhibitors” of GABA receptor binding such as phospholipids (Johnston & Kennedy, 1978) are present in mammalian brain tissue. It was 1977 and nothing was known at that time about the structure of the GABA receptor or the exact distribution of receptor binding sites in the mammalian brain. But Curtis, Duggan, Felix, and Johnston (1970) in Australia had described the first competitive antagonist of the GABA receptor. Recognizing this, Hanns and his colleague, Okada, were able to use radiolabeled bicuculline to demonstrate binding sites on synaptic membranes for the first time at the meeting (Möhler, 1979; Mohler & Okada, 1978).

I had been working on peripheral nervous tissue, namely, the rat superior cervical ganglion, at this time and had found that GABA receptors were present on neurones in this tissue and when activated produced neuronal depolarization (Bowery & Brown, 1974). This appeared to be analogous to the depolarization of primary afferent fibers produced by GABA in mammalian spinal cord (Curtis, 1978). In fact, evidence had shown that this depolarization of nerve terminals (primary afferent depolarization) was responsible for physiological inhibition of dorsal roots. Thus, activation of GABAergic interneurones within the spinal cord can reduce sensory input.

Thus far, the response to GABA in superior cervical ganglia was detected by electrophysiological surface recording from intact isolated tissue. The advent of GABA receptor binding techniques, which were adequately described at this meeting, prompted Hanns and me to consider the possibility of detecting the presence of binding sites in homogenates of ganglia. As a consequence, we arranged to do a series of experiments in his laboratory in Basel. These experiments were performed over a period of about 6 weeks during which we obtained preliminary evidence for the existence of saturable binding sites on this tissue. This culminated in studies conducted by David Hill, in my laboratory in London (Bowery, Hill, & Möhler, 1979), showing the nature of these binding sites in bovine superior cervical ganglia.

While in Basel, Hanns and I discussed in great detail about the possibility of a novel receptor for GABA existing on neurones within the brain. This was prompted by findings that my colleague, Alan Hudson, and I had obtained in isolated atria of the rat (Bowery & Hudson, 1979). There was no evidence at that time for any other GABA receptor with distinct pharmacological properties being present within the brain or elsewhere. Binding sites with different affinities had been described by, for example, Johnston and Kennedy (1978), Olsen et al. (1981), and Guidotti, Gale, Suria, and Toffano (1979), but there was no pharmacological distinction between them. In fact, evidence indicated that any separation might be due to the removal of endogenous inhibitors when neuronal membranes were extensively washed. Washing appeared to serially uncover binding sites with higher affinity for GABA.

Our studies suggested the presence of a novel receptor for GABA in synaptic membranes, the pharmacology of which is quite distinct from the classical chloride-dependent GABA receptor. The observations that led to this discovery emanated from experiments using rat-isolated atria. We hypothesized that if GABA receptor activation on neurones of superior cervical ganglia could produce the same effect on the nerve terminals of these ganglionic neurones, this would produce terminal depolarization analogous to that occurring at primary afferent terminals in the spinal cord (Curtis, 1978).

Of course, we could not examine any depolarization produced by GABA directly but instead decided to study the effect of GABA on the release of noradrenaline from atrial tissue evoked by transmural stimulation. For this purpose, we chose to look at the release of radiolabeled noradrenaline as it had been recently established that 3H-noradrenaline taken up by isolated atria was released from transmitter stores in nerve terminals within the heart tissue in response to nerve stimulation (Iversen, 1974). The results of our experiments showed that, as predicted, GABA reduced the evoked release of 3H-noradrenaline (Bowery et al., 1981; Bowery & Hudson, 1979). This was most evident in the presence of an α1 adrenoceptor antagonist to suppress feedback inhibition of noradrenaline (Bowery et al., 1981; Kalsner, 1973). We initially assumed that this inhibition by GABA was due to nerve terminal depolarization. However, when we began to examine the pharmacology of this effect, we found that the recognized GABA receptor antagonist, bicuculline, would not prevent the action of GABA (Bowery et al., 1981), and, moreover, the GABA analogue, β-chlorophenyl GABA (baclofen) acted as an agonist mimicking the action of GABA. This compound has no effect at bicuculline-sensitive receptors (see Bowery, 1993).

I remember discussing these results in detail with Hanns, and he strongly encouraged me to pursue these findings. We subsequently published our initial findings, which prompted us to discover whether this action of GABA could be detected in brain tissue. It soon became evident that we were looking at a novel receptor for GABA, which was not chloride-dependent and had a distinct pharmacological profile (Bowery, 1993). We wanted to emulate the binding studies for GABA that by now had become firmly established but could not see a way of detecting this novel site in the presence of the established GABA receptor. Using the recognized 3H-GABA binding technique in sodium-free medium and in the presence of bicuculline, no residual saturable binding was observed. The addition of cations such as calcium and nickel had no effect on this binding (Enna & Snyder, 1977). We decided that the only way forward was to obtain some radiolabeled baclofen and to examine for any saturable binding. For this, I returned to Basel not to Hanns’ laboratory at Hoffman LaRoche but to that of Helmut Bittiger at the then CIBA-Geigy laboratories.

Baclofen was first discovered by this group in an attempt to produce a GABA mimetic that might be used as a centrally active sedative/muscle relaxant. It was initially designed as a GABA analog, which, unlike GABA, would cross the blood–brain barrier (Bein, 1972; Keberle & Faigle, 1972). However, there was never any evidence to show that it acted at the chloride-dependent GABA receptor even though it produced muscle relaxation in humans. It was first marketed for the treatment of muscle rigidity in 1972 and remains the drug of choice in such conditions.

Fortunately, the CIBA-Geigy group had produced tritiated baclofen and was kind enough to provide us with a sample. They also provided us with their raw data from experiments in which they had attempted, but failed, to obtain evidence for the presence of binding sites for 3H-baclofen on synaptic membranes. All of their experiments had been conducted in Na+- and Ca2 +-free media as had been employed for 3H-GABA binding. So David Hill and I decided that we would use the same physiological medium that we had used for our release studies in isolated atria and brain slices...

Produkt-Details

• Erscheint lt. Verlag: 27.1.2015
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Gesundheitsfachberufe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zellbiologie
• ISBN-10: 0-12-802691-X / 012802691X
• ISBN-13: 978-0-12-802691-5 / 9780128026915