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

1. Auflage 2015
ISBN: 978-0-12-802692-2
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 72, 282 Seiten

Reihe: Advances in Pharmacology

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

Autoren/Hrsg.

Rudolph, Uwe

Inhaltsverzeichnis

1;Front Cover;1
2;Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part A;4
3;Copyright;5
4;Contents;6
5;Preface;10
6;Contributors;14
7;Chapter 1: The Legacy of the Benzodiazepine Receptor: From Flumazenil to Enhancing Cognition in Down Syndrome and Social ...;16
7.1;1. Introduction;17
7.1.1;1.1. A serendipitous appointment;18
7.2;2. Discovery of the Benzodiazepine Receptor;19
7.2.1;2.1. The beginning of the GABA hypothesis;19
7.2.2;2.2. Radioligand binding with 3H-diazepam;20
7.2.3;2.3. First sighting of the benzodiazepine receptor in GABAergic synapses;21
7.2.4;2.4. The benzodiazepine receptor as part of the GABAA receptor;22
7.2.5;2.5. GABAA receptor subtypes;22
7.3;3. Dr. Ziegler, a First for Flumazenil;24
7.4;4. Where are the Selective Anxiolytics?;25
7.4.1;4.1. The first generation;25
7.4.2;4.2. Toward a second-generation nonsedative anxiolytics;27
7.5;5. Role of a2 GABAA Receptors in Circuits of Risk Assessment and Fear;28
7.5.1;5.1. Anxiolysis by attenuating a negative bias;28
7.5.2;5.2. Anxiolysis by attenuating fear learning;29
7.5.3;5.3. Anxiolysis by attenuating fear expression;30
7.6;6. Comorbidity of Anxiety States and Depression: A Telling Animal Model;30
7.6.1;6.1. Toward GABAergic antidepressants;30
7.7;7. Powerful, Nonsedative GABAergic Analgesics;32
7.8;8. Cognitive Behavior Targeted via a5 GABAA Receptors;33
7.8.1;8.1. Mouse genetics of a5 GABAA receptors led the way;33
7.8.2;8.2. Restoring memory deficits with a5 GABAA receptor inverse agonists;33
7.9;9. Down Syndrome: Start of a Clinical Trial Targeting Cognitive Dysfunction;34
7.9.1;9.1. Down syndrome Ts65Dn mice: Cognitive behavior restored by a5 GABAA receptor partial inverse agonists;34
7.10;10. Autism Spectrum Disorders: Beneficial Benzodiazepine Actions at Very Low Dose;36
7.10.1;10.1. Neocortical circuit imbalance;36
7.10.2;10.2. Frequent GABA circuit dysfunctions in ASD mouse models;36
7.10.3;10.3. BTBR mouse model of autism: Effective GABA therapeutics;39
7.10.4;10.4. Dravet´s syndrome: Amelioration by GABA therapeutics;39
7.10.5;10.5. Challenges for GABA pharmacology in ASD: Finding the balance;40
7.10.6;10.6. Role of GABAA receptor subtypes;40
7.10.7;10.7. Dose-response curve;40
7.11;11. Conclusion;41
7.12;Conflict of interest;41
7.13;References;41
8;Chapter 2: Behavioral Functions of GABAA Receptor Subtypes - The Zurich Experience;52
8.1;1. Introduction: GABAA Receptor Research at the Institute of Pharmacology and Toxicology of the University of Zurich;53
8.2;2. Behavioral Functions of the .2 Subunit;55
8.3;3. Genetic Dissection of the Pharmacological Functions of GABAA Receptors Using a Subunit Knock-in Mice;56
8.4;4. Switching Efficacy from Negative to Positive Allosteric Modulation by Histidine to Arginine Point Mutations;58
8.5;5. Interaction of Benzodiazepines and Ethanol;58
8.6;6. Role of ß3-Containing GABAA Receptors in the Action of General Anesthetics;59
8.7;7. Role of a5-Containing GABAA Receptors in the Development of Tolerance;60
8.8;8. Glutamatergic Forebrain Neurons Mediate the Sedative Action of Diazepam;61
8.9;9. Memory for Location and Objects Requires a5-Containing GABAA Receptors;61
8.10;10. Diazepam-Induced Changes in Respiration: Role of a1- and a2-Containing GABAA Receptors;61
8.11;11. Modulation of Defensive Behavioral Reactivity to Mild Threat;62
8.12;12. Conclusion;63
8.13; Conflict of interest;63
8.14;Acknowledgments;64
8.15;References;64
9;Chapter 3: Allosteric Modulation of GABAA Receptors via Multiple Drug-Binding Sites;68
9.1;1. Introduction;70
9.2;2. Structure of GABAA Receptors;71
9.3;3. GABA-Binding Sites;74
9.4;4. Benzodiazepine-Binding Sites;75
9.4.1;4.1. Interaction of benzodiazepine-binding site ligands with the a+.- interface of GABAA receptors;75
9.4.2;4.2. Interaction of benzodiazepine-binding site ligands with additional binding sites at GABAA receptors;76
9.4.2.1;4.2.1. Benzodiazepine-binding sites possibly located in the transmembrane domain;76
9.4.2.2;4.2.2. Benzodiazepine-binding sites at the a+ß- interface;77
9.4.2.3;4.2.3. Benzodiazepine binding to the GABA-binding site (ß+a- interface);78
9.4.2.4;4.2.4. Benzodiazepine binding to an extracellular intrasubunit site;80
9.4.2.5;4.2.5. High-affinity flunitrazepam binding to a "non-benzodiazepine" site at a6ß2.2 receptors;80
9.5;5. Picrotoxinin-Binding Sites;81
9.6;6. Binding Sites for Anesthetics;83
9.6.1;6.1. Binding sites of anesthetics in the transmembrane domain within a or ß subunits;84
9.6.2;6.2. A propofol-binding site between TM1 and TM2 of a single ß subunit;86
9.6.3;6.3. Binding sites for etomidate, barbiturates, and propofol in the transmembrane domain at interfaces between subunits;86
9.6.3.1;6.3.1. Etomidate-binding site at the transmembrane ß+a- interfaces;86
9.6.3.2;6.3.2. Barbiturate-binding sites at the transmembrane a+ß-, .+ß-, and ß+a- interfaces;87
9.6.3.3;6.3.3. Propofol-binding sites at the transmembrane a+ß-, .+ß-, and ß+a- interfaces;87
9.6.4;6.4. A possible propofol-binding site in the intracellular loop;88
9.6.5;6.5. Steroid-binding sites in the transmembrane a+ß- interface and in the a1 intrasubunit pocket;89
9.6.6;6.6. A possible loreclezole-binding site near ß2Asn265 at the extracellular end of TM2;89
9.6.7;6.7. A possible n-octanol-binding site near ß2Asn265;91
9.6.8;6.8. Conclusions on the localization of anesthetic binding sites in GABAA receptors;91
9.6.8.1;6.8.1. Possible pitfalls of the methods used for localization of anesthetic binding sites;91
9.6.8.2;6.8.2. Summary on the localization of binding sites of various anesthetics;94
9.7;7. Alcohol-Binding Sites;95
9.7.1;7.1. Alcohol-binding sites in the transmembrane domain;95
9.7.2;7.2. Alcohol-binding sites in the extracellular a+ß- interface of a4/6ß3d receptors;96
9.8;8. Cannabinoid-Binding Site;97
9.9;9. Avermectin B1a-Binding Site;98
9.10;10. Binding Sites of Ions;99
9.11;11. Conclusion;99
9.12;Conflict of interest;102
9.13;References;102
10;Chapter 4: Regulation of GABAARs by Phosphorylation;112
10.1;1. Introduction;113
10.2;2. The .-Aminobutyric Acid Type A Receptors;114
10.3;3. Phosphorylation Sites on GABAAR;115
10.3.1;3.1. Phosphorylation in expression systems;116
10.3.1.1;3.1.1. PKA;116
10.3.1.2;3.1.2. CamKII and Src;122
10.3.1.3;3.1.3. PKC;123
10.3.1.4;3.1.4. Lessons from expression systems;124
10.3.2;3.2. Divergent effects of kinases and phosphatases on neuronal GABAARs;125
10.4;4. GABAAR-Interacting Proteins and Phosphorylation;128
10.4.1;4.1. Adaptor protein 2;128
10.4.2;4.2. Gephyrin;130
10.4.3;4.3. A-kinase anchoring protein;130
10.4.4;4.4. Phospholipase C-related inactive protein;131
10.4.5;4.5. Receptor for activated C-kinase;132
10.5;5. Phosphorylation and Allosteric Modulation;132
10.5.1;5.1. Barbiturates and benzodiazepines;133
10.5.2;5.2. Neurosteroids;134
10.6;6. Signaling Pathways that Modulate GABAAR Phosphorylation;135
10.6.1;6.1. Receptor tyrosine kinases;135
10.6.1.1;6.1.1. Brain-derived neurotrophic factor;136
10.6.1.2;6.1.2. Insulin;137
10.6.2;6.2. Glutamate receptors;139
10.6.3;6.3. Voltage-gated Ca2+ channels;140
10.6.4;6.4. Dopamine;142
10.6.5;6.5. Others;143
10.7;7. Dysregulation of GABAAR Phosphorylation in Disease;144
10.7.1;7.1. Ischemia;144
10.7.2;7.2. Epilepsy;144
10.7.3;7.3. Drug abuse;145
10.8;8. Conclusion;147
10.9;References;148
11;Chapter 5: Endozepines;162
11.1;1. Introduction;163
11.2;2. Physiological Evidence of Endozepines;164
11.3;3. Candidate Endozepines;167
11.4;4. Diazepam-Binding Inhibitor;167
11.5;5. Conclusion;171
11.6;Conflict of interest;172
11.7;References;173
12;Chapter 6: Inhibitory Neurosteroids and the GABAA Receptor;180
12.1;1. Introduction;181
12.2;2. Structure-Function of Inhibitory Neurosteroids;184
12.3;3. Physiological Effects of Inhibitory Neurosteroids at GABAARs;187
12.4;4. Potential Inhibitory Neurosteroid-Binding Sites on GABAARs;189
12.4.1;4.1. The GABAAR ion channel at the 2 position;189
12.5;5. The Potentiating Neurosteroid-Binding Site Is Unaffected by Inhibitory Neurosteroids;192
12.6;6. Inhibitory Neurosteroid-Binding Site Outside the Ion Channel-C. elegans and UNC-49;193
12.7;7. Conclusion;196
12.8;Conflict of interest;197
12.9;Acknowledgment;197
12.10;References;197
13;Chapter 7: Interactions of Flavonoids with Ionotropic GABA Receptors;204
13.1;1. Introduction;205
13.2;2. 6-Substituted Flavones;205
13.3;3. Flavan-3-ol Esters;209
13.4;4. (+)-Catechin and a4ßd GABAA Receptors;211
13.5;5. Natural Flavonoids and Related Compounds;211
13.6;6. Conclusion;214
13.7;Conflict of interest;214
13.8;Acknowledgments;214
13.9;References;214
14;Chapter 8: GABAA Receptor Partial Agonists and Antagonists: Structure, Binding Mode, and Pharmacology;216
14.1;1. Introduction;217
14.2;2. GABAAR Antagonists;219
14.2.1;2.1. Antagonists derived from bicuculline;219
14.2.2;2.2. Antagonists derived from GABA;220
14.2.3;2.3. Antagonists derived from muscimol;220
14.2.4;2.4. Antagonists derived from 4-PIOL;222
14.2.5;2.5. Pharmacophores and homology models;227
14.3;3. GABAAR Partial Agonists;232
14.3.1;3.1. The functional consequences of GABAAR partial agonism;232
14.3.2;3.2. The experimental characterization of GABAAR partial agonism;233
14.4;4. Pharmacological Applications of GABAA Antagonists;235
14.4.1;4.1. Role of GABAAR antagonists in defining tonic GABAA currents;235
14.4.2;4.2. 4-PIOL analogues and tonic inhibition;236
14.4.3;4.3. Therapeutic relevance of modulating tonic inhibition;237
14.5;5. Conclusion;237
14.6;Conflict of interest;238
14.7;Acknowledgments;238
14.8;References;238
15;Chapter 9: Closing the Gap Between the Molecular and Systemic Actions of Anesthetic Agents;244
15.1;1. Introduction;245
15.2;2. Classical Theories of General Anesthesia;247
15.3;3. Point Mutations in GABAA Receptors Affecting Anesthetic Potency;249
15.4;4. Neuroanatomical Substrates for General Anesthetics;250
15.5;5. Homeostatic Regulations in Knockout Animals;252
15.6;6. Anesthetic-Resistant Mice;253
15.7;7. The Hypnotic Action of Etomidate;255
15.8;8. Etomidate-Induced Hypnosis and Subtype-Specific Electroencephalogram Signatures;256
15.9;9. Benzodiazepine-Induced Sedation Does Not Manifest in the EEG;257
15.10;10. Different Roles of a2- and a3-Subunits in Modulating Brain Electrical Activity;259
15.11;11. Intracortical Actions of Etomidate;260
15.12;12. Actions of Etomidate in the Hippocampus;262
15.13;13. Spinal Actions of Etomidate;264
15.14;14. Anesthetic Side Effects;266
15.15;15. Multisite and Multiple Molecular Actions of General Anesthetics;267
15.16;16. Agent-Specific Actions of Anesthetics Lacking Binding Selectivity;268
15.17;17. Conclusion;269
15.18;Conflict of interest;271
15.19;Acknowledgments;271
15.20;References;271
16;Index;278

Leseproben

Chapter One 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: [e-mail] 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 a5 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...