Rudolph Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part B

1. Auflage 2015
ISBN: 978-0-12-802691-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 73, 284 Seiten

Reihe: Advances in Pharmacology

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

Autoren/Hrsg.

Rudolph, Uwe

Inhaltsverzeichnis

1;Front Cover;1
2;Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part B;4
3;Copyright;5
4;Contents;6
5;Preface;10
6;Contributors;14
7;Chapter 1: Reflections on More Than 30 Years Association with Hanns;16
7.1;1. Introduction;16
7.2;2. Conclusion;24
7.3;Conflict of Interest;24
7.4;References;24
8;Chapter 2: Significance of GABAA Receptor Heterogeneity: Clues from Developing Neurons;28
8.1;1. Introduction;29
8.1.1;1.1. Early days;31
8.1.2;1.2. GABAA receptors and GABAergic transmission in developing CNS;33
8.1.3;1.3. Switch in GABAA receptor subunit composition during development;36
8.1.4;1.4. GABAA receptors and adult neurogenesis;42
8.1.5;1.5. Significance for CNS diseases;44
8.2;2. Conclusion;47
8.3;Conflict of Interest;47
8.4;Acknowledgments;47
8.5;References;47
9;Chapter 3: Regulation of Cell Surface GABAB Receptors: Contribution to Synaptic Plasticity in Neurological Diseases;56
9.1;1. Introduction;57
9.1.1;1.1. Structural organization of GABAB receptors;58
9.1.2;1.2. GABAB receptor effector systems;60
9.1.2.1;1.2.1. Presynaptic effector systems;61
9.1.2.2;1.2.2. Postsynaptic effector systems;61
9.2;2. Phosphorylation of GABAB Receptors;62
9.2.1;2.1. cAMP-dependent protein kinase;62
9.2.2;2.2. Protein kinase C;63
9.2.3;2.3. Calcium/calmodulin-dependent kinase II;63
9.2.4;2.4. 5'-Adenosine monophosphate-activated protein kinase;64
9.3;3. Degradation of GABAB Receptors;64
9.4;4. Contribution of Altered Cell Surface GABAB Receptor Expression to Neurological Diseases;66
9.4.1;4.1. Drug addiction;67
9.4.2;4.2. Neuropathic pain;69
9.4.3;4.3. Brain ischemia;71
9.5;5. Potential Therapeutic Implications;74
9.6;6. Conclusion;76
9.7;Conflict of interest ;77
9.8;References;77
10;Chapter 4: Restoring the Spinal Pain Gate: GABAA Receptors as Targets for Novel Analgesics;86
10.1;1. Introduction;87
10.2;2. Synaptic Disinhibition in Pathological Pain;90
10.3;3. Spinal GABAAR Subtypes Mediating Antihyperalgesia: Evidence from Genetically Engineered Mice;92
10.4;4. Mechanisms of Spinal Benzodiazepine-Mediated Antihyperalgesia;95
10.4.1;4.1. Contribution of presynaptic inhibition and primary afferent depolarization;95
10.4.1.1;4.1.1. Mechanisms of presynaptic inhibition;97
10.5;5. Antihyperalgesic Action of Benzodiazepines with Improved Subtype Specificity: Preclinical Studies;98
10.5.1;5.1. Addiction;100
10.5.2;5.2. Tolerance development against antihyperalgesia;100
10.6;6. Clinical Studies on Antihyperalgesia by Benzodiazepines;101
10.7;7. Open Questions;102
10.7.1;7.1. Which GABAAR subtypes should be targeted for optimal analgesia with minimal side-effects?;102
10.7.2;7.2. Mixed GABAARs with more than one type of a subunit;103
10.8;8. Conclusion;104
10.9;Conflict of interest statement;104
10.10;Acknowledgment;104
10.11;References;104
11;Chapter 5: GABAergic Control of Depression-Related Brain States;112
11.1;1. Introduction;113
11.2;2. The GABAergic Deficit Hypothesis of MDD;115
11.3;3. GABAergic Transmission and Heritability of MDD;121
11.4;4. GABAergic Transmission in Relation to the Monoamine Deficiency Hypothesis of MDD;122
11.5;5. GABAergic Transmission in Relation to Stress-Based Etiologies of MDD;127
11.6;6. GABAergic Transmission in Relation to the Neurotrophic Deficit Hypothesis of MDD;130
11.7;7. GABAergic Transmission in Relation to Glutamatergic Etiologies of MDD;134
11.8;8. Conclusion;138
11.9;Conflict of interest ;140
11.10;Acknowledgments;140
11.11;References;140
12;Chapter 6: Mechanisms of Fast Desensitization of GABAB Receptor-Gated Currents;160
12.1;1. Introduction;161
12.2;2. Homologous Desensitization Operating at the Receptor;163
12.3;3. Homologous Desensitization Operating at the a and ß. Subunits of the G Protein;164
12.3.1;3.1. RGS-induced fast desensitization;165
12.3.2;3.2. GRK-induced fast desensitization;168
12.3.3;3.3. KCTD12-induced fast desensitization;169
12.4;4. Slow and Fast Mechanisms of Desensitization Influence Each Other;171
12.5;5. Conclusion;172
12.6;Conflict of interest ;173
12.7;Acknowledgments;173
12.8;References;174
13;Chapter 7: Allosteric Ligands and Their Binding Sites Define .-Aminobutyric Acid (GABA) Type A Receptor Subtypes;182
13.1;1. Introduction;183
13.1.1;1.1. .-Aminobutyric acid;183
13.1.2;1.2. Brief history of function/pharmacophysiology and binding of GABAA receptors;184
13.1.2.1;1.2.1. The GABA sites;186
13.1.2.2;1.2.2. The BZ sites;186
13.1.2.3;1.2.3. The picrotoxinin sites;189
13.1.2.4;1.2.4. GABAAR: Summary based on the three ligands;193
13.1.3;1.3. Identification of ligand binding sites and their three-dimensional location: Affinity labeling, mutagenesis, X-ray c...;193
13.1.3.1;1.3.1. Picrotoxin sites lead to discovery of the anesthetic sites;193
13.1.3.2;1.3.2. GABA and BZ sites at subunit interfaces;196
13.1.3.3;1.3.3. Benzodiazepine sites lead to discovery of the ethanol (EtOH)-sensitive benzodiazepine (BZ) sites, distinct from th...;197
13.1.3.4;1.3.4. Structure of GABAAR: Mutagenesis and affinity labeling to identify functional domains especially ligand binding si...;201
13.2;2. Conclusion;206
13.3;Conflict of interest ;206
13.4;Acknowledgments;206
13.5;References;206
14;Chapter 8: Diversity in GABAergic Signaling;218
14.1;1. Introduction;219
14.2;2. Factors Shaping the Neuronal Transmembrane Chloride Gradient;221
14.2.1;2.1. Resting membrane potential;221
14.2.2;2.2. K-Cl cotransporter 2;221
14.2.3;2.3. Na-K-Cl cotransporter 1;222
14.2.4;2.4. Impermeable anions;223
14.3;3. Experimental Techniques to Study Chloride Homeostasis and E-GABAA;223
14.3.1;3.1. Classical electrophysiology;224
14.3.2;3.2. Imaging;224
14.3.2.1;3.2.1. Chloride-sensitive dyes;225
14.3.2.2;3.2.2. Genetically encoded chloride sensors;225
14.3.2.3;3.2.3. Voltage-sensitive dye imaging;226
14.4;4. Variability of GABAergic Signaling;226
14.4.1;4.1. Variability in the temporal domain;226
14.4.1.1;4.1.1. Developmental timeframe;226
14.4.1.2;4.1.2. Seasonal timeframe;228
14.4.1.3;4.1.3. Day-to-day variation and circadian rhythms;229
14.4.1.4;4.1.4. Chloride homeostasis-dependent long-term plasticity;229
14.4.1.5;4.1.5. Short-term activity- dependent chloride regulation;230
14.4.2;4.2. Variability in the spatial domain;230
14.4.2.1;4.2.1. Interspecies variability;230
14.4.2.2;4.2.2. Gender differences;231
14.4.2.3;4.2.3. Region-specific chloride homeostasis;231
14.4.2.4;4.2.4. Cell type-specific chloride homeostasis;231
14.4.2.5;4.2.5. Subcellular variation in chloride handling and GABAergic signaling;232
14.5;5. Conclusion;232
14.6;Conflict of interest ;233
14.7;References;233
15;Chapter 9: The Diversity of GABAA Receptor Subunit Distribution in the Normal and Huntington´s Disease Human Brain1;238
15.1;1. Introduction;239
15.1.1;1.1. GABAA receptors;239
15.1.1.1;1.1.1. Basal ganglia;240
15.1.1.2;1.1.2. Neurochemical compartments;241
15.1.1.3;1.1.3. GABAARs in the human basal ganglia;243
15.1.1.3.1;1.1.3.1. Regional localization;243
15.1.2;1.2. GABAAR subunit localization;244
15.1.2.1;1.2.1. Regional distribution striatum (Fig.2);244
15.1.2.2;1.2.2. Regional distribution globus pallidus;246
15.1.3;1.3. GABAA receptor subunit cellular distribution (Figs.3 and 4);247
15.1.3.1;1.3.1. Striatum;247
15.1.3.1.1;1.3.1.1. Medium spiny neuron;247
15.1.3.1.2;1.3.1.2. Interneurons;248
15.1.3.2;1.3.2. Globus pallidus;250
15.1.3.3;1.3.3. Substantia nigra (Fig.5);251
15.1.3.4;1.3.4. Subunit combinations;251
15.2;2. Neuropathology of the Basal Ganglia in Huntington´s Disease;256
15.2.1;2.1. Macroscopic changes;256
15.2.2;2.2. Grading of striatal neuropathology;257
15.3;3. Cellular and Neurochemical Changes;257
15.3.1;3.1. Striatum;257
15.3.2;3.2. Globus pallidus;261
15.3.3;3.3. Substantia nigra;262
15.3.4;3.4. Parkinson´s disease;265
15.3.5;3.5. Subventricular zone and neurogenesis in Huntington´s disease;266
15.3.6;3.6. Huntington´s disease-related proteins association with GABAA receptor subunits;268
15.3.7;3.7. Overall distribution and function of the GABAA receptor in the human basal ganglia;269
15.4;Conflict of interest ;270
15.5;Acknowledgments;270
15.6;References;270
16;Index;280

Leseproben

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 a1 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, ß-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...