Transcript Neurotransmitters

Neurotransmitters
Chapter 6 of Matthews & the brainmcgill
Ach
glutamate
100 Known Neurotransmitters
• Two Classes
– Small Molecules
• Mediate Rapid Synaptic Actions
– Neuropeptides (3-36 aa)
• Modulate Slower Ongoing Synaptic Functions
Neurotransmitters
• Acetylcholine (Ach) First NT, 1926
Cholineacetyltransferase (chat)
Acetylcholinesterase hydrolyzes Ach into acetate and choline
Otto Loewi and Henry Dale
• Discovered vagus substance = Ach
• Parasympathetic NT released from CN10
vagal nerve onto heart muscle to decrease
heart rate
• Won Nobel Prize in Medicine 1936 for
identifying the chemical nature of nerve
transmission
Otto Loewi 1873-1961
Austria
• Won Nobel Prize in 1936: chemical nature of
nerve transmission
• Imprisoned in Nazi Germany 2 yrs later
• Used Nobel $$ to ransom his life-fled to England
• 1940 came to USA by being declared senile,
worked at MBL in MA and at NYU College of
Medicine
Loewi’s Experiment
According to Loewi, the idea for his key experiment came to him in his
sleep. The next day, he dissected out of frogs two beating hearts: one
with the vagus nerve which controls heart rate attached, the other heart
on its own. Both hearts were bathed in a saline solution (i.e. Ringer's
solution). By electrically stimulating the vagus nerve, Loewi made the
first heart beat slower. Then, Loewi took some of the liquid bathing the
first heart and applied it to the second heart. The application of the liquid
made the second heart also beat slower, proving that some soluble
chemical released by the vagus nerve was controlling the heart rate. He
called the unknown chemical Vagusstuff. It was later found that this
chemical corresponded to acetylcholine.
A Nobel Prize laureate fond of narrating how his monumental breakthrough
describing the theory of chemical transmission of the nervous impulse exploded in
a torrent of inspiration during a sleepless night. How, having retraced the source
of his astonishing hunch he proposed that most "intuitive" discoveries are
associated with earlier hypotheses buried deep in the unconscious mind.
3 Criteria for Neurotransmitter
• 1: the substance must be in presynaptic
neuron
• 2: Substance released by presynaptic
depolarization that is calcium depenedent
• 3: Specific receptors must be present on
post-synaptic membrane
NTs versus Hormones
• NTs effect targets only micrometers away from
site of release
• Hormones work on target organs at a distance
• Travel through blood stream
• Some hormones vasopressin & oxytocin are also
NTs
Sir Dale’s Principle
1875-1968 England
• One neuron releases 1 NT
– Holds true for amines and amino acid NT
– Started convention for adding “ergic” to NT name to
define type of neuron based on NT released from axon
• Cholineric
• Adrenergic
• peptidergic
• One neuron can release 1 classical NT and many
neuropeptides
Co-Transmitters
• Co-transmitters = 2 or more NTs present in
one synapse
• Each type of NT packaged in separate
synaptic vesicle in general
Amines
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epinephrine,
norepinephrine,
dopamine
serotonin,
histamine
Amino Acid Neurotransmitters
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Glutamic acid
Aspartate
Glycine
gaba (g-aminobutyric acid),
Peptides
• string of amino acids, endorphins
enkaphalins, substance P
• Larger molecules than amines and amino
acids
• Both classes are synthesized and transported
by different mechanisms to the synapse
NT Synaptic Vesicles
• Small Molecules
• Packaged in Small
Clear Core Vesicles
• 40-60nm across
• Neuropeptides
• Packaged in Large
Dense Core Vesicles
• 90-250nm diameter
Small Molecule NT Synthesis
• Enzymes synthesized in soma & transported
by slow axonal (0.5-5mm/day) transport to
synapse
• Used to synthesize NT at terminal
Neuropeptides Synthesis
• Enzymes and Prepropeptides precursor
synthesized in soma
• Processed in ER to propeptide
• Modified in Golgi and Packaged into
vesicles
• Transported by rapid axon transport
400mm/day
Readings in Matthews
• Chapter 20 page 465-480 NMDA Receptors
• Chapter 11 page 246-250 Metabotropic
receptors
The brainmcgill website
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Link of synapses
Synapses
Neurotransmitters
Receptor Subtypes
Glutamate/learning and memory
Long term Potentiation LTP
Biochemical reactions
Drugs and Neurotransmitters (look at good info)
Excitatory NTs
• Cause an EPSP on the post-synaptic neuron
• Glutamate is the most common CNS NT
• Aspartic acid is also a NT
Excitatory NT in CNS
Glutamate
• Most important NT for brain function
• Nearly all excitatory synapses in brain are
glutaminergic
• High levels of extracellular glutamate are
toxic to neurons
• Released from neurons after trauma
Glutamate Synthesis
• Glutamate cannot cross BBB
• Synthesized from glutamine in neurons
• Glutamine released by astrocytes into
extracellular space
• Taken up by neurons and glutaminase in
mitochondria convert it to glutamate
• Glucose can also be precursor
Glutamate Receptors
• Three major subtypes named for their
selective chemical agonist
– NMDA
• n-methyl-d-aspartate
– AMPA
• A-amino-3-hydroxy-5-methyl-4-isoxazole
propionate
– Kainate
Agonist: a drug or
compound that
mimics the action of
the naturally occurring
NT
Antagonist: a drug or
compound that inhibits
the action of the
naturally occurring NT
Glutamate Receptor Specificity
• Glutamate binds and activates all three
subtypes
• AMPA only binds & activates the AMPA
subtype
• NMDA only binds & activates NMDA
subtype
Selective Agonists: drugs that can select 1 out of many receptor subtypes
Figure 8:the neuropharmacology of glutamatergic synaptictransmission
AMPA glutamate Receptor
Subtype
• AMPA receptors opens first
in response to glutamate
binding and conducts Na and
K
• Only has NT gate
• At negative resting
membrane potential, the
opening of the channel
causes a large inward sodium
current much like NAchR
NMDA Receptor
• Has voltage and NT gate
• NMDA receptor binds
glutamate and opens but does
not conduct due to Mg2+
block of pore
• When voltage is depolarized,
then Mg2+ comes off and now
conducts current carried by
Na, K and Ca
Learning and Memory Associated with Glutamate Neurotransmission
The brainmcgill website
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Link of synapses
Synapses
Neurotransmitters
Receptor Subtypes
Glutamate/learning and memory
Long term Potentiation LTP
Biochemical reactions
Drugs and Neurotransmitters (look at good info)
Toxins bind NMDA Receptors
• Food toxins (chick peas) and plant toxins
Dopamine
• A biogenic catecholamine
– Family Includes Epinephrine,
Norepinephrine, histamine and serotonin
• Derived from tyrosine
– By tyrosine hydroxylase using oxygen to make
Dopa
• Made from Dopa into dopamine by DOPA
decarboxylase
Dopamine
• Only 0.3% of brain synapses use dopamine
• But very important in
– in movement
– pleasure seeking and avoiding bad situations
– addictive behaviors
Parkinson’s Disease is due to loss of dopamine from Substantia nigra,
part of the basal ganglia that provides input to striatum
•Levadopa, a precursor is absorbed in the small intestine
& crosses BBB
•Important for movement control
Clinical Relevance of Dopamine
• Cocaine acts to prolong dopamine in
synapses by blocking dopamine reuptake
• Dopamine used to treat shock in that it
dilates renal artery & increases cardiac
output
• Involved in drug addiction
Serotonin (5HT), Biogenic
monoamine
• Made from tryptophan, essential aa
• Neurons have tryptophan transporter
• Tryptophan 5-hydroxylase converts to
serotonin and is rate limiting step
• Catabolized by monoamine oxidase MAO
• Used by brainstem neurons that project to
frontal cortex, also regulate sleep and wake
Prozac
• Does not bind to neurotransmitter receptor
• Blocks reuptake of serotonin is the central
mechanism for stopping action 5HT
• Binds SERT, serotonin transporter
• Prolonged action of serotonin at synapses
improves mood by unknown mechanism
Serotonin in Immune System
• Involved in Allergies
• Released by Basophils
• Mediates gastrointestinal motility
Ecstasy
• damages serotonergic signaling
• MDMA, produced by Merck (3,4 Methylenedioxymethamphetamine
• Can cause toxicity by decreasing levels of
serotonin receptors, serotonin levels and
enzymes used in it synthesis.
• Mainly affects Raphe Nucleus in Pons
• The raphe axons and neurons die
Ecstasy Side Effects
• Depression, Anxiety, Panic Attacks
• Decreased cognitive function and verbal
memory
• Brain mcgill link
Excitotoxicity
• Seen after trauma, stroke, ischemia,
repeated seizures
• Too much glutamate causes neuron death
• Glutamate antagonist therapy has been
ineffective
– Due to late start of administration & neurons
die of apoptosis and inflammatory responses
Glutamate Excitotoxicity
• Large influx of calcium through NMDA
receptors
• Swelling on neurons and death
• Calcium activate proteases
• Override neurons ability to chelate and
pump out calcium and sodium
• Associated with neuronal death in ALS,
alzheimers