Download NEUROTRANSMITTERS AND RECEPTORS

NEUROTRANSMITTERS
AND RECEPTORS
The Structure of the Neuron
• Playing the piano, driving a car, or hitting a tennis ball depends, at one
level, on exact muscle coordination.
• But if we consider how the muscles can be activated so precisely, we
see that more fundamental processes are involved.
• For the muscles to produce the complex movements that make up
any meaningful physical activity, the brain has to provide the right
messages to them and coordinate those messages.
The Structure of the Neuron
• Neurons , or nerve cells, are the basic elements of the nervous system.
• Many of the body’s neurons receive signals from the environment or
relay the nervous system’s messages to muscles and other target cells,
but the vast majority of neurons communicate only with other neurons
in the elaborate information system that regulates behavior.
• The messages that travel through a neuron are electrical in nature.
Although there are exceptions, those electrical messages, or impulses ,
generally move across neurons in one direction only, as if they were
traveling on a one-way street.
How Neurons Fire
What is a synapse?
• A junction where the axon or some other portion of one cell (= presynaptic
cell) terminates on the dendrites, soma, or axon of another neuron (post
synaptic cell).
Types of synapses ( functional classification)
Two types of communicating junctions or synapses: Electrical synapses
via gap junctions, chemical synapses involving neurotransmitters
•A.Electrical synapse
•…
•B.Chemical synapse
•Almost all synapses used for signal transmission in the CNS of
human being are chemical synapses.
• i.e. first neuron secretes a chemical substance called
neurotransmitter at the synapse to act on receptor on the next
neuron to excite it, inhibit or modify its sensitivity.
Structure of an electrical synapse
Chemical synapse
Figure 48.12 A chemical synapse
CHEMICAL ACTIVITY AT SYNAPSE:
Excitatoy Postsynaptic
Potential (EPSP)
Inhibitory post-synaptic
potentials (IPSP)
• The excitatory
• Stim. of some inputs
neurotransmitter opens
[=pre-synaptic terminals]
Na+ or Ca++ channels 
 hyperpolarization of
depolarization of the area the post-synaptic memb.
under the pre-synaptic
which is the IPSP.
membrane.
Classification of neurotransmission
Fast neurotransmission
Neurotransmitter directly activates ligand-gated ion channel receptor
Neuromodulation
Neurotransmitter binds to G-protein coupled receptor to activate a
chemical signaling cascade
Synaptic inhibition
• Direct inhibition
• Post-synaptic inhibition, e.g. some interneurones in sp. cord that inhibit antagonist
muscles. Neurotransmitter secreted is Glycine.
• Occurs when an inhibitory neuron (releasing inhibitory substance) act on a postsynaptic neuron leading to  its hyperpolarization due to opening of Cl¯ [IPSPs]
and/or K+ channels.
• Indirect inhibition
--->
Indirect inhibition
• Pre-synaptic inhibition.
• This happens when an inhibitory synaptic knob lie directly on the
termination of a pre-synaptic excitatory fiber.
• The inhibitory synaptic knob release a transmitter which inhibits the
release of excitatory transmitter from the pre-synaptic fiber.
• The transmitter released at the inhibitory knob is GABA.
• The inhibition is produced by  Cl¯ and  K+. e.g. occurs in dorsal
horm  pain gating.
• Fast neurotransmission: glutamate, GABA, glycine, acetylcholine
•
Metabolism and vesicular transport
•
Reuptake and degradation
•
Receptor systems
•
Pharmacology: agonists and antagonists
•
Synaptic integration
• Neuromodulation: catecholamines, serotonin, histamine, neuropeptides
•
Overview of G-protein signaling
•
Metabolism and vesicular transport
•
Reuptake and degradation
•
Receptor systems, coupling, downstream targets
•
Pharmacology: agonists and antagonists
1.
Structure and function of receptors
Nerve
Nerve
Signal
Messenger
Receptor
Response
Nucleus
Cell
Cell
1.
Structure and function of receptors
Mechanism
Induced fit
Messenger
Messenger
Messenger
Cell
Membrane
Receptor
Receptor
Cell
Cell
Receptor
Cell
message
Message
1.
Structure and function of receptors
Chemical Messengers
Neurotransmitters: Chemicals released from nerve endings which
travel across a nerve synapse to bind with receptors on target cells,
such as muscle cells or another nerve. Usually short lived and
responsible for messages between individual cells
Hormones: Chemicals released from cells or glands and which travel
some distance to bind with receptors on target cells throughout the
body
•
Chemical messengers ‘switch on’ receptors without undergoing a reaction
• Control of ion channels
• Receptor protein is part of an ion channel protein complex
• Receptor binds a messenger leading to an induced fit
• Ion channel is opened or closed
• Ion channels are specific for specific ions (Na+, Ca2+, Cl-, K+)
• Ions flow across cell membrane down concentration gradient
• Polarises or depolarises nerve membranes
• Activates or deactivates enzyme catalysed reactions within cell
Control of ion channels
Receptor
Binding
site
Cell
membrane
Five glycoprotein subunits
traversing cell membrane
Messenger
Induced
fit
‘Gating’
(ion channel
opens)
Cationic ion channels for K+, Na+, Ca2+ (e.g. nicotinic) = excitatory
Anionic ion channels for Cl- (e.g. GABAA) = inhibitory
Cell
membrane
Figure 12.21 Neurotransmitter Functions
Figure 12.21a
Control of ion channels:
MESSENGER
ION
CHANNEL
(closed)
Cell
membrane
Cell
Ion
channel
RECEPTOR
BINDING
SITE
Lock
Gate
Ion
channel
ION
CHANNEL
(open)
Induced fit
and opening
of ion channel
Cell
membrane
Cell
membrane
Cell
Ion
channel
MESSENGER
Ion
channel
Cell
membrane
Activation of signal proteins
•
Receptor binds a messenger leading to an induced fit
•
Opens a binding site for a signal protein (G-protein)
•
G-Protein binds, is destabilised then split
messenger
induced
fit
closed
open
G-protein
split
Figure 12.21 Neurotransmitter Functions
Figure 12.21b
Activation of signal proteins
•
G-Protein subunit activates membrane bound enzyme
Binds to allosteric binding site
Induced fit results in opening of active site
•
Intracellular reaction catalysed
Enzyme
Enzyme
active site
(closed)
active site
(open)
Intracellular
reaction
Figure 12.21 Neurotransmitter Functions
Figure 12.21c
Activation of enzyme active site
•
Protein serves dual role - receptor plus enzyme
•
Receptor binds messenger leading to an induced fit
•
Protein changes shape and opens active site
•
Reaction catalysed within cell
messenger
messenger
induced
fit
closed
active site
open
intracellular reaction
closed
Neurotransmitters
• There are dozens of different neurotransmitters (NT) in
the neurons of the body.
• NTs can be either excitatory or inhibitory
• Each neuron generally synthesizes and releases a single
type of neurotransmitter
• The major neurotransmitters are indicated on the next
slide.
The classical neurotransmitters
• Amines
• Monoamines
• catecholamines (dopamine, noradrenaline)
• indoleamines (serotonin, melatonin)
• Quaternary amines
• acetylcholine
• amino acids (glutamate, GABA)
Cholinergic Synapses
• Acetylcholine is a common
transmitter.
• Synapses that have acetylcholine
transmitter are called cholinergic
synapses.
• Some neurones form more than 1
synapse.
• This is an electron
micrograph of synapses
between nerve fibres and
a neurone cell body.
Acetylcholine
ACh is a transmitter that is in a class by itself:
• It is synthesized in terminals from acetyl CoA and choline by choline
acetyltransferase.
• It is packaged in vesicles in the axon terminals.
• It can bind to two distinct receptor types: nicotinic and muscarinic.
Nicotinic receptors are seen in the skeletal muscle synapse and at synapses
within the CNS. Muscarinic receptors for ACh are also seen in the CNS and
at parasympathetic synapses on target tissues.
• After release, ACh is degraded by the enzyme acetylcholinesterase into
acetate and choline.
• The choline is taken back into the terminal by Na+-driven facilitated uptake.
What happens at a cholinergic synapse? Stage 1
• An action potential arrives at
presynaptic membrane. Voltage gated
calcium channels in the presynaptic
membrane open, calcium ions enter
the presynaptic neurone.
What happens at a cholinergic synapse? Stage 2
• Calcium ions cause synaptic
vesicles to fuse with the
presynaptic membrane,
releasing acetylcholine into the
synaptic cleft.
What happens at a cholinergic synapse? Stage 3
• Acetylcholine diffuses cross the
synaptic cleft and binds to specific
neuroreceptor sites in the post
synaptic membrane.
What happens at a cholinergic synapse? Stage 4
• Sodium channels open. Sodium ions
diffuse into the postsynaptic
membrane causing depolarisation,
which may initiate an action
potential.
What happens at a cholinergic synapse? Stage 5
• Acetylcholinesterase breaks down
acetylcholine. The products diffuse
back into the presynaptic neurone
where acetycholine is
resynthesised using ATP from the
mitochondria.
Amino acids: The workhorses of the
neurotransmitter family
Glutamate - the primary excitatory neurotransmitter in brains
GABA (Gamma-amino-butyric-acid) - the primary inhibitory
neurotransmitter
The fabulous glutamate receptor
Activation of NMDA receptor can cause changes in the
numbers of AMPA receptors – a mechanism for learning?
The fabulous GABA receptor
Multiple binding sites
GABA receptor binding sites
GABA synthesis, release, reuptake, degradation
1.
2.
3.
4.
5.
GABA is formed by removal of
carboxyl group of glutamate, by
the enzyme GAD
GABA is packaged into synaptic
vesicles by VIAAT and released
by depolarization
GABA may be taken up by
nerve terminal by GAT proteins
for repackaging into synaptic
vesicles
GABA may be taken up by glial
cells, where it undergoes
reconversion to glutamate
(amine group is transferred to aketoglutarate, generating
glutamate and succinic
semialdehyde)
Glutamate is transported back
into nerve terminal, where it
serves as precursor for new
GABA synthesis
a-ketoglutarate glutamate
Major Neurotransmitters in the Body
Neurotransmitter
Role in the Body
Acetylcholine
A neurotransmitter used by the spinal cord neurons to control muscles and
by many neurons in the brain to regulate memory. In most instances,
acetylcholine is excitatory.
Dopamine
The neurotransmitter that produces feelings of pleasure when released by
the brain reward system. Dopamine has multiple functions depending on
where in the brain it acts. It is usually inhibitory.
GABA
(gamma-aminobutyric acid)
The major inhibitory neurotransmitter in the brain.
Glutamate
The most common excitatory neurotransmitter in the brain.
Glycine
A neurotransmitter used mainly by neurons in the spinal cord. It probably
always acts as an inhibitory neurotransmitter.
Norepinephrine
Norepinephrine acts as a neurotransmitter and a hormone. In the
peripheral nervous system, it is part of the flight-or-flight response. In the
brain, it acts as a neurotransmitter regulating normal brain processes.
Norepinephrine is usually excitatory, but is inhibitory in a few brain areas.
Serotonin
A neurotransmitter involved in many functions including mood, appetite,
and sensory perception. In the spinal cord, serotonin is inhibitory in pain
pathways.
NIH Publication No. 00-4871
Drugs Interfere with Neurotransmission
•
Drugs can affect synapses at a variety of sites and in a variety of
ways, including:
1. Increasing number of impulses
2. Release NT from vesicles with or without
impulses
3. Block reuptake or block receptors
4. Produce more or less NT
5. Prevent vesicles from releasing NT
Drugs That Influence Neurotransmitters
Change in Neurotransmission
Effect on Neurotransmitter
release or availability
Drug that acts this way
increase the number of impulses
increased neurotransmitter
release
nicotine, alcohol, opiates
release neurotransmitter from
vesicles with or without impulses
increased neurotransmitter
release
amphetamines
methamphetamines
release more neurotransmitter in
response to an impulse
increased neurotransmitter
release
nicotine
block reuptake
more neurotransmitter present in
synaptic cleft
cocaine
amphetamine
produce less neurotransmitter
less neurotransmitter in synaptic
cleft
probably does not work this way
prevent vesicles from releasing
neurotransmitter
less neurotransmitter released
No drug example
block receptor with another
molecule
no change in the amount of
neurotransmitter released, or
neurotransmitter cannot bind to
its receptor on postsynaptic
neuron
LSD
caffeine
NIH Publication No. 00-4871
Ways that drugs can agonize
• Stimulate release
• receptor binding
• inhibition of reuptake
• inhibition of deactivation
• promote synthesis
Ways that drugs can antagonize
• Block release
• receptor blocker
• prevent synthesis
Drugs and the Synapse
• Amphetamine stimulate dopamine synapses by increasing the
release of dopamine from the presynaptic terminal.
• Cocaine blocks the reuptake of dopamine, norepinephrine, and
serotonin.
• Methylphenidate (Ritalin) also blocks the reuptake of dopamine
but in a more gradual and more controlled rate.
Drugs and the Synapse
• Nicotine stimulates one type of acetylcholine receptor
known as the nicotinic receptor.
• Nicotinic receptors are found in the central nervous
system, the nerve-muscle junction of skeletal muscles and
in the nucleus accumbens (facilitate dopamine release).
Effect of nicotine and atropine
Drugs and the Synapse
• Ecstasy increases the release of dopamine at low doses that
account for its stimulant properties.
• Ecstasy increases the release of serotonin at higher doses
accounting for its hallucinogenic properties.
• Research indicates ecstasy use may contribute to higher
incidences of anxiety and depression as well as memory loss
and other cognitive deficits.
Drugs and the Synapse
• The brain produces peptides called endorphins.
• Endorphin synapses may contribute to certain kinds of
reinforcement by inhibiting the release of GABA indirectly.
• Inhibiting GABA indirectly releases dopamine.
• Endorphins attach to the same receptors to which opiates
attach.
How does alcohol affect synapses?
• Alcohol has multiple effects on neurons. It alters neuron membranes,
ion channels, enzymes, and receptors.
• It binds directly to receptors for acetylcholine, serotonin, and gamma
aminobutyric acid (GABA), and glutamate.
• We will focus on GABA and its receptor.
GABA and the GABA Receptor
• GABA is a neurotransmitter that has an inhibitory effect on neurons.
• When GABA attaches to its receptor on the postsynaptic membrane,
it allows Cl- ions to pass into the neuron.
• This hyperpolarizes the postsynaptic neuron to inhibit transmission
of an impulse.
Alcohol and the GABA Receptor
• When alcohol enters the brain, it binds to GABA receptors and
amplifies the hyperpolarization effect of GABA.
• The neuron activity is further diminished
• This accounts for some
of the sedative affects
of alcohol
science.howstuffworks.com/ alcohol.htm
Catecholamines
Dopamine
Subtantia nigra and
Parkinson’s disease
Mesocorticolimbic
system and
schizophrenia
Receptor specificity
Catecholamines
Noradrenergic pathways in the brain
-locus coeruleus
Acetylcholine
Cholinergic pathways in the brain
-basal forebrain, neuromuscular junction
• Acetylcholine is transmitted within cholinergic pathways that are
concentrated mainly in specific regions of the brainstem and are
thought to be involved in cognitive functions, especially memory.
Severe damage to these pathways is the probable cause of
Alzheimer’s disease.
• There is a link between acetylcholine and Alzheimer's disease: There
is something on the order of a 90% loss of acetylcholine in the brains
of people suffering from Alzheimer's, which is a major cause of
senility.
Serotonin
Serotonergic pathways in the brain
-raphe, 15 subtypes, Prozac and depression
• Low serotonin levels leads to an increased appetite for carbohydrates
and trouble sleeping, which are also associated with depression and
other emotional disorders. It has also been tied to migraines.
• Low serotonin levels are also associated with decreased immune
system function.
• In addition to mood control, serotonin has been linked with a wide
variety of functions, including the regulation of sleep, pain
perception, body temperature, blood pressure and hormonal activity
• Within the brain, serotonin is localized mainly in nerve pathways
emerging from the raphe nuclei, a group of nuclei at the centre of the
reticular formation in the Midbrain, pons and medulla.
• These serotonergic pathways spread extensively throughout the
brainstem , the cerebral cortex and the spinal cord .
• People with too little GABA tend to suffer from anxiety disorders, and
drugs like Valium work by enhancing the effects of GABA. Lots of
other drugs influence GABA receptors, including alcohol and
barbiturates. If GABA is lacking in certain parts of the brain, epilepsy
results.