Molecular neuroscience

Book Cover......Page 1
Half-Title......Page 2
Title......Page 3
Copyright......Page 4
Contents......Page 5
Abbreviations......Page 9
Preface......Page 14
Chapter 1 Introduction......Page 15
 2.2  The amino acid sequence of a protein can be deduced by sequencing its DNA......Page 17
 2.4  Separation of DNA fragments by size......Page 18
 2.5  DNA molecules can be joined using ligases......Page 19
 2.6  rDNA is introduced into bacterial cells for cloning......Page 20
  2.7.1   Plasmid vectors......Page 21
  2.7.2  Phage vectors......Page 22
 2.8  Several methods have been devised to sequence nucleic acids......Page 23
  2.9.1  cDNA is made from total mRNA......Page 25
  2.9.2  A cDNA library can be screened using synthetic oligonucleotide probes......Page 26
  2.9.3  Hybridization screening can be used to localize the required clone......Page 27
 2.10  The nicotinic cholinergic receptor was sequenced by probing a cDNA library......Page 28
  2.10.1  Subunit structure was inferred from the amino acid sequence......Page 29
  2.10.2  High homology was demonstrated between subtypes......Page 31
  2.10.3  Functional receptor can be expressed in Xenopus oocytes......Page 32
 3.2  Many neurotransmitters can be located by histochemistry......Page 35
 3.4  Some neurotransmitters can be located by specific uptake mechanisms......Page 36
 3.6  In situ hybridization can determine patterns of gene expression......Page 37
 3.8  Differential hybridization and subtracted cDNA libraries can measure differences in gene expression......Page 38
 3.9  The polymerase chain reaction can produce large amounts of a specific DNA......Page 39
 3.10  Single-cell PCR......Page 41
 3.11  mRNA differential display uses PCR to study changes in gene expression......Page 42
 3.12  A large number of genes expressed in human brain have been identified......Page 43
  4.1.1  Different channels can have very different properties......Page 45
  4.2.1  The electroplax sodium channel was cloned using cDNA libraries......Page 46
  4.2.2  Aspects of the secondary structure can be inferred from the amino acid sequence......Page 47
  4.2.3  Mammalian sodium channels contain additional subunits......Page 48
  4.3.1  Channel activation involves the movement of gating charges......Page 49
  4.3.3  Pore-lining residues and ion conductance can be identified using TTX......Page 50
  4.4.1 Calcium channels are distributed differently and can be blocked by toxins......Page 51
  4.5.1  The α1-subunit from skeletal muscle was the first to be cloned......Page 52
  4.5.3  Other calcium channel subunits have also been cloned......Page 53
 4.6  How similar are sodium and calcium channels?......Page 54
 4.7  There is a large diversity of voltage-gated potassium channels......Page 55
  4.7.2  Transient VDKCs control firing frequency of neurons......Page 56
 4.8  Genes for potassium channels have been identified in naturally occurring mutant flies......Page 57
  4.8.1  Potassium channels are homologous to voltage-dependent Na+channels......Page 58
  4.8.2  Pore-lining residues have been found......Page 59
  4.8.4  Potassium channels contain auxiliary proteins......Page 60
 4.9  Not all K+ channels belong to the same superfamily......Page 61
  5.2.1  A 4TM topology for nAChR is most likely......Page 67
 5.3  The M2 segments contribute to the ion pore......Page 69
  5.3.2  Channel gating currently is a mystery......Page 71
 5.4  GABA is the major CNS inhibitory transmitter......Page 72
  5.5.2  Barbiturate-binding site......Page 73
  5.5.5  Additional GABA receptor interactions......Page 74
  5.6.2  Multiple subunits exist for GABAA receptors......Page 75
 5.7  GABAC receptors......Page 77
  5.8.2  Ionotropic AMPA/kainate receptors are only weakly homologous to other ligand-gated ion channels......Page 78
  5.9.2  Mutant channels allow the pore-forming region to be defined......Page 80
  5.10.1 NMDA receptors harbor binding sites for several classes of molecule......Page 81
  5.10.3  NMDA receptors probably have a topology resembling other ionotropic glutamate receptors......Page 82
  5.10.4  The NMDAR1 subunit has several isoforms derived by alternative splicing......Page 83
  5.11.2  NMDARs appear to be developmentally regulated......Page 84
 6.3  G protein-linked receptors form a superfamily of receptors......Page 86
 6.4  G protein-linked receptors share a common structure......Page 88
  6.4.1  Metabotropic glutamate receptors have evolved separately......Page 89
  6.4.2  Ligand-binding domains vary between different G protein-linked receptors......Page 90
  6.4.4  Desensitization of the receptors is associated with phosphorylation......Page 91
  6.5.1  The are four families of α-subunits......Page 92
  6.5.2  The β- and γ-subunits are less diverse......Page 93
  6.7.1  Adenylate cyclase can be dually regulated by G proteins......Page 94
  6.7.3  G protein activation of phospholipase C produces multiple second messengers......Page 95
  6.8.1  βγ-subunits can also affect the activity of intracellular enzymes......Page 96
  6.9.1  Direct membrane-delimited regulation by α-subunits has been shown......Page 97
  6.10.2  RTKs are involved in long-term intracellular events......Page 98
 6.12  Mutations in 7TM receptors underlie a variety of diseases......Page 99
 6.13  Dopamine receptors have been implicated in schizophrenia......Page 100
 7.1  Introduction......Page 103
 7.4  Neurotransmitter release is calcium dependent......Page 104
  7.5.1  P-type calcium channels are responsible for neurotransmitter release at the mammalian neuromuscular junction......Page 106
 7.6  A large number of proteins have been identified in nerve terminals......Page 107
 7.8  Vesicle recruitment may involve synapsin......Page 108
 7.9  SNAPs and SNAREs are involved in docking and then priming vesicles for release......Page 109
 7.11  Synaptotagmin may be the calcium sensor involved in the final exocytotic event......Page 111
 7.13  Neurexins are a target for neurotoxins......Page 112
 7.15  Refilling of vesicles with neurotransmitter occurs via an antiport mechanism......Page 113
 7.17  Lambert-Eaton myasthenic syndrome is a failure of neurotransmitter release......Page 115
 8.1  The hippocampus is required for episodic memory......Page 119
 8.2  Long-term potentiation is an activity-dependent increase in synaptic strength......Page 120
  8.2.2  NMDARs are implicated in associative LTP......Page 121
  8.2.3  Calcium is the second messenger mediating LTP......Page 122
 8.4  Protein kinases are activated during LTP......Page 123
  8.4.2  Transcription factors are important in plasticity......Page 124
 8.5  Invertebrates currently provide the most complete evidence for nuclear signaling via cAMP in plasticity......Page 125
 8.7  Presynaptic mechanisms for induction of LTP......Page 129
  8.7.1 Morphological changes may explain some characteristics of LTP......Page 130
  8.7.2  There are a number of possible retrograde messengers......Page 131
  8.7.4  The specificity of long-lasting LTP requires synaptic tags......Page 132
 8.8  Long-term depression is a synaptic weakening......Page 134
  8.8.2  Phosphatases are important in LTD......Page 135
 8.9  Voltage-dependent channels are implicated in plasticity......Page 136
 8.10  LTP may be a molecular model for some types of learning......Page 138
 8.11  Epilepsy is a chronic hyperexcitable state......Page 139
  8.11.2  The signature of the epileptic brain is abnormal burst firing......Page 140
  8.11.4  Ionotropic glutamate receptors are implicated in epileptogenesis......Page 141
  8.11.6  What produces epilepsy in vivo?......Page 142
  9.2.1 The gene for HD has been located and sequenced......Page 146
  9.2.4  HD can be mimicked experimentally......Page 147
  9.3.1  Cell death may be due to an increase in intracellular Ca2+ concentration......Page 148
  9.3.3  Other neurological diseases may involve excitotoxicity......Page 149
 9.4  Parkinson’s disease also causes degeneration of specific neurons......Page 150
  9.4.1  PD may be caused by an environmental factor......Page 151
  9.4.2  PD may be due to free radical damage......Page 152
  9.5.1  Alzheimer’s disease has a wide pattern of neuronal degeneration......Page 153
  9.6.1  APP is associated with early-onset AD......Page 154
 9.7  The amyloid hypothesis depends on the abnormal deposition of βA......Page 155
 9.9  ApoE interacts with both βA and tau in an isoform-specific manner......Page 157
 9.11  New therapies may be based on understanding the molecular basis of AD......Page 158
 9.12  Common paths to oxidative stress and free radical damage in neurodegenerative disease......Page 159
 Appendix 2.  Single-letter code and three-letter abbreviations for amino acids......Page 162
 Appendix 3.  Some second messenger-activated enzymes......Page 163
 Chapter 6......Page 170
 Chapter 9......Page 171
Index......Page 172