Neurotransmitters

Copyright 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins

Neuroscience: Exploring the Brain, 3e

Chapter 6: Neurotransmitter Systems


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


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



Studying Transmitter Localization

Transmitters and Transmitter-Synthesizing Enzymes

Immunocytochemistry localize molecules to cells



Studying Transmitter Localization (Contd)

In situ hybridization

Localize synthesis of protein or peptide to a cell (detect mRNA)



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



Studying Synaptic Mimicry

Qualifying condition: Molecules evoking same response as neurotransmitters

Microionophoresis: Assess the

postsynaptic actions

Microelectrode: Measures effects on

membrane potential



Studying Receptor Subtypes

Neuropharmacology

Agonists and antagonists

e.g., ACh receptors

Nicotinic, Muscarinic

Glutamate receptors

AMPA, NMDA, and kainite



Studying Receptors (Contd)

Ligand-binding methods

Identify natural receptors using radioactive ligands

Can be: Agonist, antagonist, or chemical neurotransmitter



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


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



Cholinergic (ACh) Neurons



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)



Serotonergic (5-HT) Neurons

Amine neurotransmitter

Derived from tryptophan

Regulates mood, emotional behavior, sleep

Selective serotonin reuptake inhibitors (SSRIs) - Antidepressants

Synthesis of serotonin



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



Other Neurotransmitter Candidates and Intercellular Messengers

ATP: Excites neurons; Binds to purinergic receptors

Endocannabinoids

Retrograde messengers


Transmitter-Gated Channels Ionotropic receptors

Introduction

Fast synaptic transmission

Sensitive detectors of chemicals and voltage

Regulate flow of large currents

Differentiate between similar ions


Transmitter-Gated Channels

The Basic Structure of Transmitter-Gated Channels

Pentamer: Five protein subunits



Amino Acid-Gated Channels

Glutamate-Gated Channels

AMPA, NMDA, kainite




Voltage dependent NMDA channels




GABA-Gated and Glycine-Gated Channels

GABA mediates inhibitory transmission

Glycine mediates non-GABA inhibitory transmission

Bind ethanol, benzodiazepines, barbiturates


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



The Ubiquitous G-Proteins

GTP-binding (G-) protein

Signal from receptor to effector proteins



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



GPCR Effector Systems

The Shortcut Pathway

From receptor to G-protein to ion channel; Fast and local



GPCR Effector Systems

Second Messenger Cascades

G-protein: Couples neurotransmitter with downstream enzyme activation



GPCR Effector Systems (Contd)

Push-pull method (e.g., different G proteins for stimulating or inhibiting adenylyl cyclase)




Some cascades split

G-protein activates PLC generates DAG and IP3 activate different effectors




Signal amplification




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


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


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


End of Presentation

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Neurotransmitters