This 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
This 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
Front Cover 1
Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part A 4
Copyright 5
Contents 6
Preface 10
Contributors 14
Chapter 1: The Legacy of the Benzodiazepine Receptor: From Flumazenil to Enhancing Cognition in Down Syndrome and Social ... 16
1. Introduction 17
1.1. A serendipitous appointment 18
2. Discovery of the Benzodiazepine Receptor 19
2.1. The beginning of the GABA hypothesis 19
2.2. Radioligand binding with 3H-diazepam 20
2.3. First sighting of the benzodiazepine receptor in GABAergic synapses 21
2.4. The benzodiazepine receptor as part of the GABAA receptor 22
2.5. GABAA receptor subtypes 22
3. Dr. Ziegler, a First for Flumazenil 24
4. Where are the Selective Anxiolytics? 25
4.1. The first generation 25
4.2. Toward a second-generation nonsedative anxiolytics 27
5. Role of a2 GABAA Receptors in Circuits of Risk Assessment and Fear 28
5.1. Anxiolysis by attenuating a negative bias 28
5.2. Anxiolysis by attenuating fear learning 29
5.3. Anxiolysis by attenuating fear expression 30
6. Comorbidity of Anxiety States and Depression: A Telling Animal Model 30
6.1. Toward GABAergic antidepressants 30
7. Powerful, Nonsedative GABAergic Analgesics 32
8. Cognitive Behavior Targeted via a5 GABAA Receptors 33
8.1. Mouse genetics of a5 GABAA receptors led the way 33
8.2. Restoring memory deficits with a5 GABAA receptor inverse agonists 33
9. Down Syndrome: Start of a Clinical Trial Targeting Cognitive Dysfunction 34
9.1. Down syndrome Ts65Dn mice: Cognitive behavior restored by a5 GABAA receptor partial inverse agonists 34
10. Autism Spectrum Disorders: Beneficial Benzodiazepine Actions at Very Low Dose 36
10.1. Neocortical circuit imbalance 36
10.2. Frequent GABA circuit dysfunctions in ASD mouse models 36
10.3. BTBR mouse model of autism: Effective GABA therapeutics 39
10.4. Dravet´s syndrome: Amelioration by GABA therapeutics 39
10.5. Challenges for GABA pharmacology in ASD: Finding the balance 40
10.6. Role of GABAA receptor subtypes 40
10.7. Dose-response curve 40
11. Conclusion 41
Conflict of interest 41
References 41
Chapter 2: Behavioral Functions of GABAA Receptor Subtypes - The Zurich Experience 52
1. Introduction: GABAA Receptor Research at the Institute of Pharmacology and Toxicology of the University of Zurich 53
2. Behavioral Functions of the .2 Subunit 55
3. Genetic Dissection of the Pharmacological Functions of GABAA Receptors Using a Subunit Knock-in Mice 56
4. Switching Efficacy from Negative to Positive Allosteric Modulation by Histidine to Arginine Point Mutations 58
5. Interaction of Benzodiazepines and Ethanol 58
6. Role of ß3-Containing GABAA Receptors in the Action of General Anesthetics 59
7. Role of a5-Containing GABAA Receptors in the Development of Tolerance 60
8. Glutamatergic Forebrain Neurons Mediate the Sedative Action of Diazepam 61
9. Memory for Location and Objects Requires a5-Containing GABAA Receptors 61
10. Diazepam-Induced Changes in Respiration: Role of a1- and a2-Containing GABAA Receptors 61
11. Modulation of Defensive Behavioral Reactivity to Mild Threat 62
12. Conclusion 63
Conflict of interest 63
Acknowledgments 64
References 64
Chapter 3: Allosteric Modulation of GABAA Receptors via Multiple Drug-Binding Sites 68
1. Introduction 70
2. Structure of GABAA Receptors 71
3. GABA-Binding Sites 74
4. Benzodiazepine-Binding Sites 75
4.1. Interaction of benzodiazepine-binding site ligands with the a+.- interface of GABAA receptors 75
4.2. Interaction of benzodiazepine-binding site ligands with additional binding sites at GABAA receptors 76
4.2.1. Benzodiazepine-binding sites possibly located in the transmembrane domain 76
4.2.2. Benzodiazepine-binding sites at the a+ß- interface 77
4.2.3. Benzodiazepine binding to the GABA-binding site (ß+a- interface) 78
4.2.4. Benzodiazepine binding to an extracellular intrasubunit site 80
4.2.5. High-affinity flunitrazepam binding to a "non-benzodiazepine" site at a6ß2.2 receptors 80
5. Picrotoxinin-Binding Sites 81
6. Binding Sites for Anesthetics 83
6.1. Binding sites of anesthetics in the transmembrane domain within a or ß subunits 84
6.2. A propofol-binding site between TM1 and TM2 of a single ß subunit 86
6.3. Binding sites for etomidate, barbiturates, and propofol in the transmembrane domain at interfaces between subunits 86
6.3.1. Etomidate-binding site at the transmembrane ß+a- interfaces 86
6.3.2. Barbiturate-binding sites at the transmembrane a+ß-, .+ß-, and ß+a- interfaces 87
6.3.3. Propofol-binding sites at the transmembrane a+ß-, .+ß-, and ß+a- interfaces 87
6.4. A possible propofol-binding site in the intracellular loop 88
6.5. Steroid-binding sites in the transmembrane a+ß- interface and in the a1 intrasubunit pocket 89
6.6. A possible loreclezole-binding site near ß2Asn265 at the extracellular end of TM2 89
6.7. A possible n-octanol-binding site near ß2Asn265 91
6.8. Conclusions on the localization of anesthetic binding sites in GABAA receptors 91
6.8.1. Possible pitfalls of the methods used for localization of anesthetic binding sites 91
6.8.2. Summary on the localization of binding sites of various anesthetics 94
7. Alcohol-Binding Sites 95
7.1. Alcohol-binding sites in the transmembrane domain 95
7.2. Alcohol-binding sites in the extracellular a+ß- interface of a4/6ß3d receptors 96
8. Cannabinoid-Binding Site 97
9. Avermectin B1a-Binding Site 98
10. Binding Sites of Ions 99
11. Conclusion 99
Conflict of interest 102
References 102
Chapter 4: Regulation of GABAARs by Phosphorylation 112
1. Introduction 113
2. The .-Aminobutyric Acid Type A Receptors 114
3. Phosphorylation Sites on GABAAR 115
3.1. Phosphorylation in expression systems 116
3.1.1. PKA 116
3.1.2. CamKII and Src 122
3.1.3. PKC 123
3.1.4. Lessons from expression systems 124
3.2. Divergent effects of kinases and phosphatases on neuronal GABAARs 125
4. GABAAR-Interacting Proteins and Phosphorylation 128
4.1. Adaptor protein 2 128
4.2. Gephyrin 130
4.3. A-kinase anchoring protein 130
4.4. Phospholipase C-related inactive protein 131
4.5. Receptor for activated C-kinase 132
5. Phosphorylation and Allosteric Modulation 132
5.1. Barbiturates and benzodiazepines 133
5.2. Neurosteroids 134
6. Signaling Pathways that Modulate GABAAR Phosphorylation 135
6.1. Receptor tyrosine kinases 135
6.1.1. Brain-derived neurotrophic factor 136
6.1.2. Insulin 137
6.2. Glutamate receptors 139
6.3. Voltage-gated Ca2+ channels 140
6.4. Dopamine 142
6.5. Others 143
7. Dysregulation of GABAAR Phosphorylation in Disease 144
7.1. Ischemia 144
7.2. Epilepsy 144
7.3. Drug abuse 145
8. Conclusion 147
References 148
Chapter 5: Endozepines 162
1. Introduction 163
2. Physiological Evidence of Endozepines 164
3. Candidate Endozepines 167
4. Diazepam-Binding Inhibitor 167
5. Conclusion 171
Conflict of interest 172
References 173
Chapter 6: Inhibitory Neurosteroids and the GABAA Receptor 180
1. Introduction 181
2. Structure-Function of Inhibitory Neurosteroids 184
3. Physiological Effects of Inhibitory Neurosteroids at GABAARs 187
4. Potential Inhibitory Neurosteroid-Binding Sites on GABAARs 189
4.1. The GABAAR ion channel at the 2 position 189
5. The Potentiating Neurosteroid-Binding Site Is Unaffected by Inhibitory Neurosteroids 192
6. Inhibitory Neurosteroid-Binding Site Outside the Ion Channel-C. elegans and UNC-49 193
7. Conclusion 196
Conflict of interest 197
Acknowledgment 197
References 197
Chapter 7: Interactions of Flavonoids with Ionotropic GABA Receptors 204
1. Introduction 205
2. 6-Substituted Flavones 205
3. Flavan-3-ol Esters 209
4. (+)-Catechin and a4ßd GABAA Receptors 211
5. Natural Flavonoids and Related Compounds 211
6. Conclusion 214
Conflict of interest 214
Acknowledgments 214
References 214
Chapter 8: GABAA Receptor Partial Agonists and Antagonists: Structure, Binding Mode, and Pharmacology 216
1. Introduction 217
2. GABAAR Antagonists 219
2.1. Antagonists derived from bicuculline 219
2.2. Antagonists derived from GABA 220
2.3. Antagonists derived from muscimol 220
2.4. Antagonists derived from 4-PIOL 222
2.5. Pharmacophores and homology models 227
3. GABAAR Partial Agonists 232
3.1. The functional consequences of GABAAR partial agonism 232
3.2. The experimental characterization of GABAAR partial agonism 233
4. Pharmacological Applications of GABAA Antagonists 235
4.1. Role of GABAAR antagonists in defining tonic GABAA currents 235
4.2. 4-PIOL analogues and tonic inhibition 236
4.3. Therapeutic relevance of modulating tonic inhibition 237
5. Conclusion 237
Conflict of interest 238
Acknowledgments 238
References 238
Chapter 9: Closing the Gap Between the Molecular and Systemic Actions of Anesthetic Agents 244
1. Introduction 245
2. Classical Theories of General Anesthesia 247
3. Point Mutations in GABAA Receptors Affecting Anesthetic Potency 249
4. Neuroanatomical Substrates for General Anesthetics 250
5. Homeostatic Regulations in Knockout Animals 252
6. Anesthetic-Resistant Mice 253
7. The Hypnotic Action of Etomidate 255
8. Etomidate-Induced Hypnosis and Subtype-Specific Electroencephalogram Signatures 256
9. Benzodiazepine-Induced Sedation Does Not Manifest in the EEG 257
10. Different Roles of a2- and a3-Subunits in Modulating Brain Electrical Activity 259
11. Intracortical Actions of Etomidate 260
12. Actions of Etomidate in the Hippocampus 262
13. Spinal Actions of Etomidate 264
14. Anesthetic Side Effects 266
15. Multisite and Multiple Molecular Actions of General Anesthetics 267
16. Agent-Specific Actions of Anesthetics Lacking Binding Selectivity 268
17. Conclusion 269
Conflict of interest 271
Acknowledgments 271
References 271
Index 278
The Legacy of the Benzodiazepine Receptor
From Flumazenil to Enhancing Cognition in Down Syndrome and Social Interaction in Autism
Hanns Möhler*,†,1 * Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
† Department of Chemistry and Applied Biosciences, Federal Institute of Technology (ETH), Zurich, Switzerland
1 Corresponding author: email address: mohler@pharma.uzh.ch
Abstract
The study of the psychopharmacology of benzodiazepines continues to provide new insights into diverse brain functions related to vigilance, anxiety, mood, epileptiform activity, schizophrenia, cognitive performance, and autism-related social behavior. In this endeavor, the discovery of the benzodiazepine receptor was a key event, as it supplied the primary benzodiazepine drug-target site, provided the molecular link to the allosteric modulation of GABAA receptors and, following the recognition of GABAA receptor subtypes, furnished the platform for future, more selective drug actions. This review has two parts. In a retrospective first part, it acknowledges the contributions to the field made by my collaborators over the years, initially at Hoffmann-La Roche in Basle and later, in academia, at the University and the ETH of Zurich. In the second part, the new frontier of GABA pharmacology, targeting GABAA receptor subtypes, is reviewed with special focus on nonsedative anxiolytics, antidepressants, analgesics, as well as enhancers of cognition in Down syndrome and attenuators of symptoms of autism spectrum disorders. It is encouraging that a clinical trial has been initiated with a partial inverse agonist acting on α5 GABAA receptors in an attempt to alleviate the cognitive deficits in Down syndrome.
Keywords
Benzodiazepines
Anxiolytics
Depression
Analgesics
Cognitive dysfunction
1 Introduction
This chapter is dedicated with gratitude to my collaborators and colleagues over the years, who shared the goal of advancing GABA pharmacology for the benefit of patients suffering from mental and neurological disorders such as anxiety, sleep disorders, epileptiform activity, pain, and memory impairment. From my time at Hoffmann-La Roche, I am most indebted to Toshikazu Okada, Grayson Richards, Pari Malherbe, and Peter Schoch, and from my subsequent group in Zurich to Uwe Rudolph, now at Harvard University; Bernhard Lüscher, now at Pennsylvania State University; Jean-Marc Fritschy, Florence Crestani, and Dietmar Benke at the University of Zurich; and Detlev Boison, now at Legacy Research Institute in Portland. It was their commitment and expertise which made the visions and accomplishments for novel therapies possible. I am most grateful to have had the good fortune of their company. Today, the legacy of the benzodiazepine receptor manifests itself in the search for nonsedating anxiolytics, rapidly acting antidepressants, nonsedative analgesics, cognition enhancers for Down syndrome, and enhancers of social interaction in autism spectrum disorders (ASD), as outlined below. For further reviews on these and related topics, see Rudolph and Möhler (2014), Möhler (2011, 2012a, 2013), Rudolph and Knoflach (2011), Olsen and Sieghart (2008), and Fritschy and Panzanelli (2014).
1.1 A serendipitous appointment
While brain research in the late 1960s was an exciting new field, training in the area was not available at German universities where I had studied biochemistry. My PhD focused on the structure/function relationships of enzymes and was largely completed at Michigan State University, where I had the opportunity to accompany Karl Decker, my PhD supervisor and mentor in Biochemistry from the University of Freiburg, Germany, on his sabbatical. A Cold Spring Harbor course in Neuroscience in 1970, with James Watson, David van Essen, Steven Kuffler, and John Nichols among the speakers, was my introduction to neuroscience and strengthened my conviction to change fields and move into brain research. Metabolic compartmentation in the brain was the first topic I studied as a postdoc with Robert Balazs at the Medical Research Council laboratories in London. While academic positions in neuroscience in Germany remained practically nonexistent, I learned that Hoffmann-La Roche in Basle was expanding its Neuroscience Research with a focus on specific neurotransmitter systems. As the neurotransmitters dopamine and serotonin were already being intensively studied at Roche by Guiseppe Bartholini and Mosé da Prada, I was offered a position to investigate gamma-aminobutyric acid (GABA), a compound which had only recently received the blessing as a bona fide neurotransmitter (for review, see Bowery & Smart, 2006). This rather serendipitous appointment was to have an impact on my entire scientific career. The drug-dependent regulation of GABAergic inhibitory transmission in the brain through GABAA receptors remained the focus of my research even after moving back to academia.
My start at Roche in 1973 coincided with Sam Enna coming to Basle with his wife Colleen and baby daughter Anne for postdoctoral research with Alfred Pletscher, head of global research at Roche. It was the beginning of a friendship which Moira and I continue to cherish. During my time at Roche, I continued teaching at the University of Freiburg as a requirement for promotion to Professor of Biochemistry. I left Roche in 1988 after having received multiple highly attractive offers from academia, including one from the Max Planck Institute of Psychiatry in Munich. After much consideration, I accepted the chair of Pharmacology, holding it jointly at the Medical Faculty of the University of Zurich and the Department of Chemistry and Applied Biosciences at the Swiss Federal Institute of Technology (ETH) Zurich, which included the directorship of the Institute of Pharmacology. The legacy of my time at Roche, where biochemists, electrophysiologists, morphologists, pharmacologists, chemists, and clinicians regularly met around the table, was the establishment of a multidisciplinary group in Zurich with a deep commitment to turning advances in basic neuroscience into therapeutic opportunities.
2 Discovery of the Benzodiazepine Receptor
2.1 The beginning of the GABA hypothesis
To this day, benzodiazepine-type drugs continue to be widely used in medicine as anxiolytics, sedative/hypnotics, muscle relaxants, and anticonvulsants. In the years following the introduction of the first benzodiazepines, Librium and Valium, to therapy in 1960 and 1962, respectively, initial attempts to explain their neurophysiological effects by actions on catecholamine, indolamine, or glycine neurotransmission remained unconvincing, as high doses were required. At the same time, electrophysiological studies pointed to a GABAergic mechanism of action. Diazepam was found by several groups to efficiently enhance presynaptic inhibition in spinal cord and cuneate nucleus (Schlosser, 1971; Schmidt, 1971; Schmidt, Vogel, & Zimmerman, 1967; Stratten & Barnes, 1971). The neurons which mediated presynaptic inhibition were presumed to operate with GABA as their neurotransmitter, based on the ability of picrotoxin and bicuculline to reduce this type of inhibition (Eccles, 1964). At Roche, the effect of diazepam on presynaptic inhibition was found to be stimulus-dependent. As the GABA concentration was not affected by the drug (Polc, Möhler, & Haefely, 1974) it was concluded: “…that benzodiazepines probably enhance presynaptic inhibition and that this effect requires not only the presence of GABA but is also dependent on an activity of GABAergic neurons” (Haefely et al., 1975). Apart from the Roche scientists, Erminio Costa's group at the NIMH in Washington, testing diazepam in the regulation of pharmacologically induced convulsions and tremors, arrived at similar conclusions, stating that “…through its action on GABA, diazepam may elicit its muscle relaxation and antitremorigenic and anticonvulsant action” (Costa, Guidotti, & Mao, 1975). It was at the 1974 ACNP meeting that both groups presented convincing evidence for their hypothesis that benzodiazepines may act by enhancing GABAergic neurotransmission (Costa et al., 1975; Haefely et al., 1975). However, molecular description of the mechanism of action and drug target had to await the discovery of the benzodiazepine-binding site.
2.2 Radioligand binding with 3H-diazepam
Encouraged by the novel strategy of using radioligand binding to study biological receptors (Enna & Snyder, 1975; Möhler & Okada, 1977a; Pert & Snyder, 1973), I decided to apply this principle to benzodiazepine drugs and obtained permission for 3H-diazepam to be synthesized at Roche to the highest possible specific radioactivity, which amounted to 14 Ci/mmol. Experimentally, a specific 3H-diazepam-binding site was discovered exclusively in membrane fractions of the CNS. It was termed the benzodiazepine receptor, as it represented the common target site of the pharmacologically and therapeutically active benzodiazepine drugs (Möhler & Okada, 1977b). This conclusion was based on the highly significant correlations (p < 0.01 to...
| Erscheint lt. Verlag | 12.1.2015 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Gesundheitsfachberufe |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie | |
| Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
| Naturwissenschaften ► Biologie ► Zellbiologie | |
| ISBN-10 | 0-12-802692-8 / 0128026928 |
| ISBN-13 | 978-0-12-802692-2 / 9780128026922 |
| Haben Sie eine Frage zum Produkt? |
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