Download Chapter 06 - Neurotransmitter Systems

Neuroscience: Exploring the Brain, 3e
Chapter 6: Neurotransmitter Systems
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Introduction
• Three classes of neurotransmitters
– Amino acids, amines, and peptides
• Many different neurotransmitters
• Defining particular transmitter systems
– By the molecule, synthetic machinery, packaging,
reuptake and degradation, etc.
• Acetylcholine (Ach)
–
First identified neurotransmitter
• Nomenclature (-ergic)
– Cholinergic and noradrenergic
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
• Neurotransmitter - three criteria
– Synthesis and storage in presynaptic neuron
– Released by presynaptic axon terminal
– Produces response in postsynaptic cell
• Mimics response produced by release of
neurotransmitter from the presynaptic neuron
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
• Studying Transmitter Localization
– Transmitters and Transmitter-Synthesizing Enzymes
• Immunocytochemistry – localize molecules to
cells
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
• Studying Transmitter Localization (Cont’d)
• In situ hybridization
• Localize synthesis of protein or peptide to a cell
(detect mRNA)
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
• Studying Transmitter Release
– Transmitter candidate: Synthesized and
localized in terminal and released upon
stimulation
– CNS contains a diverse mixture of synapses that
use different neurotransmitters
– Brain slice as a model
• Kept alive in vitro  Stimulate synapses,
collect and measure released chemicals
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
• Studying Synaptic Mimicry
–
Qualifying condition: Molecules evoking same response as
neurotransmitters
–
Microionophoresis: Assess the postsynaptic actions
–
Microelectrode: Measures effects on membrane potential
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
• Studying Receptor Subtypes
–
Neuropharmacology
• Agonists and antagonists
• e.g., ACh receptors
• Nicotinic, Muscarinic
• Glutamate receptors
• AMPA, NMDA, and
kainite
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
• Studying Receptors (Cont’d)
– Ligand-binding methods
• Identify natural receptors using radioactive ligands
• Can be: Agonist, antagonist, or chemical
neurotransmitter
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
• Studying Receptors (Cont’d)
– Molecular analysis- receptor protein classes
• Transmitter-gated ion channels
• GABA receptors
• 5 subunits, each made with 6 different
subunit polypeptides
• G-protein-coupled receptors
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
• Evolution of neurotransmitters
– Neurotransmitter molecules
• Amino acids, amines, and peptides
• Dale’s Principle
– One neuron, one neurotransmitter
• Co-transmitters
– Two or more transmitters released from one nerve
terminal
– An amino acid or amine plus a peptide
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
• Cholinergic (ACh) Neurons
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
• Cholinergic (ACh) Neurons
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
• Catecholaminergic Neurons
–
Involved in movement, mood, attention,
and visceral function
–
Tyrosine: Precursor for three amine
neurotransmitters that contain catechol
group
• Dopamine (DA)
• Norepinephrine (NE)
• Epinephrine (E, adrenaline)
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
• Serotonergic (5-HT) Neurons
–
Amine neurotransmitter
• Derived from tryptophan
–
Regulates mood, emotional behavior, sleep
• Selective serotonin reuptake inhibitors (SSRIs) Antidepressants
–
Synthesis of serotonin
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
• Amino Acidergic Neurons
– Amino acidergic neurons have amino acid
transporters for loading synaptic vesicles.
– Glutamic acid decarboxylase (GAD)
• Key enzyme in GABA synthesis
• Good marker for GABAergic neurons
• GABAergic neurons are major of synaptic
inhibition in the CNS
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
• Other Neurotransmitter
Candidates and Intercellular
Messengers
– ATP: Excites neurons;
Binds to purinergic
receptors
– Endocannabinoids
– Retrograde messengers
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Transmitter-Gated Channels
‘Ionotropic receptors’
• Introduction
– Fast synaptic transmission
– Sensitive detectors of chemicals and voltage
– Regulate flow of large currents
– Differentiate between similar ions
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Transmitter-Gated Channels
• The Basic Structure of Transmitter-Gated Channels
– Pentamer: Five protein subunits
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Transmitter-Gated Channels
• Amino Acid-Gated Channels
– Glutamate-Gated Channels
• AMPA, NMDA, kainite
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Transmitter-Gated Channels
• Amino Acid-Gated Channels
– Voltage dependent NMDA
channels
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Transmitter-Gated Channels
• Amino Acid-Gated Channels
– GABA-Gated and Glycine-Gated Channels
• GABA mediates inhibitory transmission
• Glycine mediates non-GABA inhibitory transmission
• Bind ethanol, benzodiazepines, barbiturates
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and
Effectors
• Three steps
– Binding of the neurotransmitter to the receptor
protein
– Activation of G-proteins
– Activation of effector systems
• The Basic Structure of G-Protein-Coupled Receptors
(GPCRs)
– Single polypeptide with seven membrane-spanning
alpha-helices
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and
Effectors
• The Ubiquitous G-Proteins
– GTP-binding (G-) protein
– Signal from receptor to effector proteins
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and
Effectors
• The Ubiquitous G-Proteins (Cont’d)
– Five steps in G-protein operation
• Inactive: Three subunits - , , and  - “float” in
membrane ( bound to GDP)
• Active: Bumps into activated receptor and
exchanges GDP for GTP
• G-GTP and G - Influence effector proteins
• G inactivates by slowly converting GTP to GDP
• G recombine with G-GDP
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and
Effectors
• GPCR Effector Systems
– The Shortcut Pathway
• From receptor to G-protein to ion channel; Fast
and local
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and
Effectors
• GPCR Effector Systems
– Second Messenger Cascades
• G-protein: Couples neurotransmitter with
downstream enzyme activation
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and
Effectors
• GPCR Effector Systems (Cont’d)
• Push-pull method (e.g., different G
proteins for stimulating or inhibiting
adenylyl cyclase)
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and
Effectors
• GPCR Effector Systems (Cont’d)
• Some cascades split
• G-protein activates PLC generates
DAG and IP3 activate different
effectors
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and
Effectors
• GPCR Effector Systems (Cont’d)
• Signal amplification
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and
Effectors
• GPCR Effector Systems (Cont’d)
– Phosphorylation and Dephosphorylation
• Phosphate groups added to or removed from a protein
• Changes conformation and biological activity
– The Function of Signal Cascades
• Signal amplification by GPCRs
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Divergence and Convergence
in Neurotransmitter Systems
• Divergence
– One transmitter activates
more than one receptor
subtype greater
postsynaptic response
• Convergence
– Different transmitters
converge to affect same
effector system
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Concluding Remarks
• Neurotransmitters
– Transmit information between neurons
– Essential link between neurons and effector cells
• Signaling pathways
– Signaling network within a neuron somewhat
resembles brain’s neural network
– Inputs vary temporally and spatially to increase
and/or decrease drive
– Delicately balanced
– Signals regulate signals- drugs can shift the
balance of signaling power
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
End of Presentation
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins