Neurotransmitters
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Transcript of Neurotransmitters
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neuroscience: Exploring the Brain, 3e
Chapter 6: Neurotransmitter Systems
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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
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
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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
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
Studying Transmitter Localization
Transmitters and Transmitter-Synthesizing Enzymes
Immunocytochemistry localize molecules to cells
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
Studying Transmitter Localization (Contd)
In situ hybridization
Localize synthesis of protein or peptide to a cell (detect mRNA)
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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
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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
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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
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
Studying Receptors (Contd)
Ligand-binding methods
Identify natural receptors using radioactive ligands
Can be: Agonist, antagonist, or chemical neurotransmitter
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Studying Neurotransmitter Systems
Studying Receptors (Contd)
Molecular analysis- receptor protein classes
Transmitter-gated ion channels
GABA receptors
5 subunits, each made with 6 different subunit polypeptides
G-protein-coupled receptors
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
Evolution of neurotransmitters
Neurotransmitter molecules
Amino acids, amines, and peptides
Dales Principle
One neuron, one neurotransmitter
Co-transmitters
Two or more transmitters released from one nerve terminal
An amino acid or amine plus a peptide
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
Cholinergic (ACh) Neurons
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Neurotransmitter Chemistry
Cholinergic (ACh) Neurons
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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)
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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
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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
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
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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
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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
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Transmitter-Gated Channels
The Basic Structure of Transmitter-Gated Channels
Pentamer: Five protein subunits
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Transmitter-Gated Channels
Amino Acid-Gated Channels
Glutamate-Gated Channels
AMPA, NMDA, kainite
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Transmitter-Gated Channels
Amino Acid-Gated Channels
Voltage dependent NMDA channels
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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
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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
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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
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and Effectors
The Ubiquitous G-Proteins (Contd)
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
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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
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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
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and Effectors
GPCR Effector Systems (Contd)
Push-pull method (e.g., different G proteins for stimulating or inhibiting adenylyl cyclase)
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and Effectors
GPCR Effector Systems (Contd)
Some cascades split
G-protein activates PLC generates DAG and IP3 activate different effectors
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and Effectors
GPCR Effector Systems (Contd)
Signal amplification
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
G-Protein-Coupled Receptors and Effectors
GPCR Effector Systems (Contd)
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
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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
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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 brains 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
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Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
End of Presentation