Download GABA A Receptor

Neurotransmitters
Dennis M. Peffley, Ph.D., J.D.
Professor of Biochemistry
General Design of the Nervous System
• CNS; more than 100 billion neurons
• Incoming signals enter via synapses
located mostly on neuronal
dendrites and the cell body.
• Few hundred up to as many as
200,000 synaptic connections
from input fibers (dendrites)
• Output signals by way of a single
axon leaving the neuron
Typical Motor Cortex Neuron
Physiologic Anatomy of the Synapse
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Ventral motor neuron from the ventral horn of the spinal cord
– Composed of three major parts
– Cell body
– Single axon
• extends from the soma into a peripheral nerve that
leaves the spinal cord
– Dendrites
• great numbers of branching projections
– 10,000 to 200,000 synaptic knobs (presynaptic terminals) on
surfaces of the dendrites and soma of the motor neuron.
• Ends of nerve fibrils that originate from other neurons
– some are excitatory and others are inhibitory
Neuronal Synapses – Chemical Synapses
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Chemical synapses use diffusible
transmitter molecules to
communicate messages between
two cells.
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The first chemical synapse to be
described was the neuromuscular
junction (a nerve-muscle synapse)
Represents a single presynaptic terminal on the membrane of a postsynaptic neuron. A synaptic cleft separates the presynaptic terminal from
the postsynaptic terminal. The transmitter vesicles and mitochondria are important to the excitatory or inhibitory functions
Transmitter substances released from the transmitter vesicles either excite or inhibit the postsynaptic neuron depending on whether the
neuron contains excitatory receptors or inhibitory receptors, respectively.
Mitochondria provide ATP that supplies energy for neurotransmitter synthesis.
Action of the Transmitter Substance on the
Postsynaptic Neuron Receptor Proteins
Membranes of postsynaptic neurons have receptor proteins. These have two
important functions:
1. Binding component
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protrudes outward from the membrane and into the synaptic cleft –
binds the neurotransmitter
2. Ionophore component
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passes all the way through the postsynaptic membrane to the interior of
the postsynaptic neuron.
The ionophore is one of two types:
1. Ion channel
• allows passage of specified types of ions through the membrane
2. Second messenger activator
• a molecule that protrudes into the cell cytoplasm and activates one or
more substances inside the postsynaptic neuron.
Ion Channels
Two Types of Channels
1. Cation Channels (Excitatory) - allow passage of
sodium ions when opened but sometimes allow
potassium and/or calcium ions as well
– When cation channels open they allow positively
charged sodium ions to enter and the positive
electrical charges will in turn excite this neuron
2.
Anion Channels (Inhibitory) - that allow mainly
chloride ions to pass
– Opening anion channels allows negative electrical
charges to enter that inhibit the neuron.
Second Messenger System in
Postsynaptic Neurons
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Ions channels are not suitable for causing prolonged postsynaptic neuronal changes
(such as those needed for memory and other prolonged changes) because they
close within millisecond
Activation of second messenger systems in the postsynaptic neuronal cell itself
achieves long term effects
The most common second messenger regulation in neurons occurs through Gproteins
A G-protein is attached to the portion of the receptor that protrudes into the interior of
the cells
The G-protein consists of three components which function in this order:
1. α-component, activated portion of the G-protein
2. β and γ-components attached to the α-component and inside of the cell
membrane adjacent to the receptor protein
3. Nerve impulse causes the α-component of the G-protein to separate from β
and γ-components and is free to move within the cell cytoplasm.
Second Messenger System in
Postsynaptic Neurons
Four changes can occur with the activation of Gproteins
1.
Opening specific ion channels through
the postsynaptic cell membrane – shown
is the opening of the potassium channel
(prolonged opening)
2.
Activation of cAMP or cGMP in the
neuronal cell – this can activate highly
specific metabolic processes in the
neuron and can initiate chemical results
that include long-term changes in cell
structure that alter long term excitability
3.
Activation of one or more intracellular
enzmes
4.
Activation of gene transcription – can
initiate formation of new proteins within
the neuron that change the metabolic
activity or structure
Steps and Mechanisms Common to
All Chemical Synapses
1. Neurotransmitter molecules are packaged into membranous vesicles, and the
vesicles are concentrated and docked at the presynaptic terminal.
1. The presynaptic membrane depolarizes, usually as the result of an action
potential.
1. The depolarization causes voltage-gated Ca2+ channels to open and
allows Ca2+ ions to flow into the terminal.
1. The resulting increase in [Ca2+] triggers fusion of vesicles with the
presynaptic membrane.
1. The transmitter is released into the extracellular space in quantized amounts
and diffuses passively across the synaptic cleft.
1. Some of the transmitter molecules bind to receptors in the postsynaptic
membrane, and the activated receptors trigger a postsynaptic event, usually
the opening of an ion channel or the activation of a G protein – coupled
signal cascade.
1. Transmitter molecules diffuse away from postsynaptic receptors and are
eventually cleared away by 1) continued diffusion, 2) enzymatic
degradation, or 3) active uptake into cells.
Ionotropic and Metatropic
Acetylcholine Receptors
The major difference between the neuromuscular
junction and neuronal synapses is the type of
neurotransmitter used.
All skeletal neuromuscular junctions use
acetylcholine (ACh)
A.
Nicotinic AChR - a ligand-gated channel (ionotropic)
on the postsynaptic membrane. In muscle the end result
would be muscle contraction.
A.
Muscarinic AChR - which is coupled to a heterotrimeric
G protein (muscarinic). In a cardiac muscle the end
result would be decreased heart rate.
Variations of the Synaptic
Communication in the Brain
Originate From Different:
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Neuronal transmitters
Receptor types
Signal Pathways
Time courses of synaptic interaction
Time Courses of Synaptic Events
Boron & Boulpaep, Medical Physiology
EM of Synapses in the Cochlear Nucleus
• Most presynaptic terminals arise from
axons
• can form synapses on any part
of a neuron.
Example: (Right) Three presynaptic terminals are filled with
vesicles and make contact with the same postsynaptic dendrite
postsynaptic densities are indicated by arrows.
Commons Types of Synapses
• Refers to the site on which the axon will
synapse
• Axodendritic – on dendrite
• Axosomatic – on soma (cell body)
• Axoaxonic – on axon
Postsynaptic Side
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In the CNS, in more than 90% of all excitatory
synapses, the postsynaptic site is a dendritic
spine.
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Spine Contents:
• Transmitter receptors
• Structural proteins
• Endocytic proteins
• Glycolytic proteins
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Spine Action:
• Increase the opportunity for a dendrite to
form synapses
• Isolate (electrically or chemically) individual
synapses from the rest of the cell.
Sensory Part of the Nervous System – Sensory Neurons
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Sensory experiences that excite sensory receptors
Examples
– Visual receptors in the eyes
– Auditory receptors in the ears
– Tactile receptors on the body surface
Sensory experiences result in:
– Immediate reactions
– Memories
Organization
– Sensory information enters the CNS via peripheral nerves
and is conducted to multiple sensory areas in the brain:
• Spinal cord (multiple levels)
• Reticular system of the medulla, pons, and mid-brain
• Cerebellum
• Thalamus
• Cerebral cortex
Motor Part of the Nervous System - Effectors
The nervous system controls various
bodily activities
• contraction of skeletal muscles
• contraction of smooth muscles in
organs
• secretion of active chemical substances
by exocrine and endocrine glands
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These activities collectively constitute
motor functions – muscles and glands
are called effectors because they
function to carry out functions dictated
by integrated nerve signals
Modulatory Systems
• Several systems of neurons regulate the general
excitability of the CNS. Each of these modulatory
systems use a different neurotransmitter
– A small set of neurons (several thousand) forms the center of
the system
– Neurons of the disperse systems arise from the central core of
the brain
– Neurons interact via their axons spreading across the brain
Use of Transmitters by Diffusely Distributed Neuron
Systems in Modulating General Excitability of the Brain
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Modulatory systems use different neurotransmitters
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Axons are widely dispersed, diffuse and somewhat
meandering synaptic connections to carry out a simple
message in the vast brain regions
Clinical Relevance
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The activity of psychoactive disorders seem to involve
alterations in one or more of the modulatory
systems.
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Spatially focused networks are utilized by the
brain to carry out many sensory, motor, and
cognitive functions that require fast, specific,
spatially organized neural networks
Example – a detailed spatially focused
network of neurons allows you to read the text
on this slide or play the piano.
Modulatory systems regulate other functions
such as falling asleep, waking up, becoming
attentive, or changing mood (these represent
more general brain alterations)
Spatial Focusing = Specific (rapid) actions
Modular Focusing = general (slow) actions
Modulatory Systems
Consists of four diffusely connected systems of central neurons that use
distinct modulatory transmitters
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Modulatory systems of the brain are distinct anatomically and biochemically
Separate systems use:
– norepinephrine,
– serotonin (5-hydroxytryptamine)
– dopamine
– Ach
– Histamine
All tend to use metabotropic (muscarinic) receptors
– coupled to adenylate cyclase or Phospholipase C through G proteins
Norepinephrine-based Modulatory System
Locus coeruleus
• ~12,000 neurons
• Innervate almost every part of the brain
– just one neuron from this locus can
make more than 250,000 synapses
• Actions
– Regulation of attention
– Arousal and sleep-wake cycles
– Learning and memory
– Anxiety
– Pain
– Mood
– Brain metabolism
Serotonin-based Modulatory System
Raphe Nuclei (9)
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Project to different brain regions
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Collectively innervate most of the CNS
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Cells of the raphe nuclei fire most rapidly during wakefulness; they are
quietest during sleep.
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Actions
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Mood
Emotional behavior
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Many hallucinogenic drugs such as LSD exert effects through interaction
with serotonergic systems
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Clinical Relevance
Serotonin may also be involved in clinical depression
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drug used to treat depression (fluoxitine or Prozac) block serotonin reuptake and prolong serotonin action in the brain.
Both locus coeruleus and the raphe nucli are part of the ascending
reticular activating system – implicate the reticular core of the
brainstem in processes that arouse and waken the forebrain
Dopaminnergic-based Modulatory System
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Scattered throughout the CNS
Two closely related groups of have characteristics of the diffuse
modulatory system
– Substantia nigra – (midbrain); its projects axons to the basal
ganglia
• facilitate initiation of voluntary movement
– Clinical Relevance
– Degeneration of dopamine-containing cells in the
substantia nigra produces the motor disorders of
Parkinson disease
– Ventral tegmental area of the midbrain – innervate part of the
fore brain (prefrontal cortex and parts of the limbic system)
• Reinforcement or reward
• drug addiction
• psychiatric disorders (schizophrenia)
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Rx. Members of the class of antipsychotic drugs called
neuroleptics are antagonists of certain dopamine receptors
Acetylcholine-based Modulatory System
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Acetyl choline is a familiar transmitter of the
neuromuscular junction and autonomic nervous system
Within the brain are two major diffuse modulatory
cholinergic systems
– Basal Forebrain Complex
• innervates the hippocampus and all of the
neocortex
– Pontomesencephalotegmenal cholinergic complex
• innervates the dorsal thalamus and parts of the
forebrain
Involved in general brain excitability during arousal and
sleep-wake cycles
Possible learning and memory formation
Actual function remains unknown
Neurotransmitter Systems of the Brain
Small Neurotransmitters
• Amino Acids: glutamic acid, gamma-aminobutyric acid
(GABA)and glycine
• Monoamines : acetylcholine, serotonin (5-hydroxytryptamine),
and histamine
• Catecholamines: dopamine, norepinephrine, epinephrine
• Purine derivatives: ATP
The small transmitters are, as a rule, each stored and released by separate sets of neurons.
Small-Molecule Transmitters
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Acetylcholine
– Terminals of large pyramidal cell from the motor cortex
– Different types of neurons in the basal ganglia
– Motor neurons innervating skeletal muscle
– Preganglionic neurons of parasympathetic nervous system
– Some postganglionic neurons in the sympathetic nervous system
– Mostly has an excitatory effect but can have an inhibitory effect on some peripheral
parasympathetic nerve endings such as inhibition of the heart by the vagus nerves
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Norepinephrine is secreted by terminal of neurons whose cell bodies are located in the
brain stem, hypothalamus, and locus ceruleus
– Norepinephrine activates excitatory receptors but in a few areas it activates
inhibitory receptors instead
– Norepinephrine is also secreted by most postganglionic neurons of the sympathetic
nervous system
Small-Molecule Transmitters
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Dopamine is secreted by neurons that originate in the substantia nigra
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Glycine is secreted mainly at synapses in the spinal cord
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It is believed to always cause inhibition
Glutamate is secreted by presynaptic terminals in many sensory
pathways entering the CNS
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It is believed to always act as an inhibitory transmitter
GABA is secreted by nerve terminals in the spinal cord, cerebellum,
basal ganglia and many areas of the cortex
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The effect of dopamine is generally inhibition
It always causes excitation
Serotonin is secreted by nuclei that originate in the median raphe of the
brain stem and project to many brain and spinal cord areas
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Serotonin acts as an inhibitor of pain pathways in the cord
An inhibitor action in higher regions of the nervous system is believed to help
control the mood of the person
Neurotransmitter Systems of the Brain
Large-molecule transmitters are proteins or neuroactive
peptides
• Endorphins (endogenous substance with morphine-like
actions) are neuroactive peptides that include small peptides
called enkephalins.
– The peptides are usually stored and released from the same
neurons as one of the small transmitters >> co-localization
of neurotransmitters.
Electrical events during neuronal excitation – basis for
understanding excitatory postsynaptic potential (EPSP) and
inhibitory postsynaptic potential (IPSP)
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The resting membrane potential for the soma of a spinal
motor neuron is about -65 millivolts – less than the -90
millivolts for large peripheral nerve fibers and skeletal
muscle fibers
– The lower voltage is important because it allows
both positive and negative control of the degree of
excitability of the neuron
– Decreasing the voltage to a less negative value
makes the membrane of the neuron more excitable
while increasing this voltage to a more negative value
makes the neuron less excitable.
Sodium ion concentration is high in the extracellular
fluid (142 mEq/L) but low inside the neuron (14 mEq/L)
Potassium ion consentration is high inside the neuronal
stroma (intracellular fluid) (120 mEq/L) but low in the
extracellular fluid (4.5 mEq/L)
Chloride ion concentration is high in the extracellular
fluid (107 mEq/L) and low inside the neuron (8 mEq/L)
Effect of Excitation on the Postsynaptic Membrane
Excitatory Postsynaptic Potential
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(A) a resting neuron with an unexcited presynaptic
terminal resting on its surface
(B) a presynaptic terminal that has secreted an
excitatory transmitter into the cleft between the
terminal and neuronal somal membrane
Excitatory transmitter acts on excitatory receptor to
increase the membrane’s permeability to Na+
Sodium ions diffuse rapidly inside of the
membrane
Influx of Na+ neutralizes part of the negativity of
the resting membrane potential – the resting
membrane potential goes from -65 to -45 millivolts
The positive increase in voltage above the
normal resting neuronal potential (or less
negative value) is called the excitatory
postsynaptic potential or EPSP – this is a value
of +20 millivolts
Spatial Summation in Neurons
Threshold of Firing for an EPSP to Occur
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Excitation of a single presynaptic terminal on a
neuron surface is insufficient to excite a neuron
Many presynaptic terminals are usually stimulated
at the same time
Although these terminal are spread over wide areas
of the neuron, their effects can still summate –
they can add to one another until neuronal
excitation does occur
The effect of summing simultaneous
postsynaptic potentials by activating multiple
terminals on widely spaced areas of neuronal
membranes is call spatial summation.
Effect of Inhibitory Synapses on the Postsynaptic Membrane
inhibitory Postsynaptic Potential
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Inhibitory synapses open mainly chloride channels
Interior membrane potential becomes more negative –
approaching the -70 millivolt level
Opening potassium channels achieves the same effect
Both chloride influx and potassium efflux increase the
degree of intracellular negativity – this is call
hyperpolarization
Inhibits neurons because the membrane potential is
even more negative than the normal intracellular
potential
– Called an inhibitory postsynaptic potential or
IPSP.
(C) the membrane potential is 5 millivolts more negative than normal and is
therefore an IPSP of -5 millivolts – this will inhibit transmission of the nerve
signal through the synapse.
Neurotransmitter Systems
Neural synapses are represented by their input to the
pyramidal neuron of the cerebral cortex
1. Excitatory synapses: Fast excitatory synapses in the
brain use glutamate or aspartate: glutamatergic
synapses
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These amino acids bind to a group of fast, ligand-gated cation
channels >> generate an excitatory postsynaptic potential
(EPSP).
Neurotransmitter Systems
2. Inhibitory synapses: The inhibitory transmitters
GABA and glycine bind to receptors that gate Cl- selective channels
3. Modulatory synapses: neuromodulator + membrane
receptor + G-protein >> intracellular signal cascade
EPSPs in the Brain Are Mediated
by Glutamate-Gated Channels
• Glutamate can act on four major classes of receptors,
one is a G-protein coupled or metabotropic receptor, and
the others are ion channels or ionotropic receptors
– Metabotropic receptors have seven membrane-spanning
segments and are linked to heterotrimeric G proteins

Ionotropic glutamate receptors
 AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid),
 NMDA (N-methyl-D-aspartate),
 Kainate
Boron & Boulpaep,
Medical Physiology

Ionotropic receptors
Permeable to:
AMPA ----------------------------Na+, K+, (Ca2+ rarely) >> fast excitation
NMDA --------------------------- Na+, K+, Ca2+
Kainate --------------------------- Na+, K+
Boron & Boulpaep, Medical Physiology
Glutamate-Gated Channels
IPSPs in the Brain Are Mediated by the
GABAA Receptor
• GABA and glycine - two major synaptic inhibitors in the CNS
• Both the GABAA and the glycine receptors are ionotropic
receptors (Cl- selective)
• GABAB receptor is a G-protein coupled metabotropic receptor
(linked to either the opening of K+ or suppression of Ca2+
channels).
GABAA Receptor
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Because of the need for control of inhibition, GABAA receptor
has other binding sites for different chemicals
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The probable natural modulators of GABAA receptor are the
metabolites of progesterone, corticosterone, and
testosterone (steroids)
Rx. Benzodiazepines (i.e.,diazepam –Valium-) and barbiturates (i.e., Phenobarbital) can also bind to
these specific binding sites on the GABAA receptor channel
 Benzodiazepines increase the frequency, and barbiturates increase the duration of channel
opening.
 Benzodiazepines can also increase the Cl- conductance of the GABAA receptor.
Effects of Drugs on Synaptic Transmission
Many drugs increase the excitability of neurons and others decrease excitability
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Caffeine, theophylline, and theobromine (found in coffee, cocoa) all increase neuronal
excitability – by reducing the threshold for excitation of neurons.
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Strychnine increases excitability of neurons by inhibiting the action of some normally
inhibitory transmitter substances – decreases inhibitory effect of glycine in the spinal
cord.
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Therefore, the effects of excitatory transmitters becomes overwhelming and neurons go
into rapidly repetitive discharge resulting in severe tonic muscle spasms
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Anesthetics increase neuronal membrane threshold for excitation and thereby
decrease synaptic transmission at many points in the nervous system – the lipid soluble
nature of anesthetics could change the neuronal membrane structure making them less
responsive to excitatory agents.
– Basically you need more neurotransmitter to fire, but since more is not made it stops
working.
Effects of Acidosis or Alkalosis
on Synaptic Transmission
• Alkalosis greatly increases neuronal excitability
• An increase in arterial blood pH from 7.4 to 7.8 or 8.0
often causes cerebral epileptic seizures because of
increased neuron excitability
• Acidosis depresses neuronal activity
– A fall in pH from 7.4 to 7.0 usually causes a comatose state
– A very severe diabetic or uremic acidosis results in
development of coma.
Effect of Hypoxia
• Cessation of oxygen for only a few seconds results in
complete inexcitability of some neurons
• Interruption of the brain’s blood flow for only a few
seconds causes a person to lose consciousness.