Download receptors

 Neurotransmitter Release:
exocytosis and endocytosis
1.
Transmitter synthesized and stored
2.
Action Potential
3.
Depolarization: open voltage-gated
Ca2+ channels
4.
Ca2+ enter cell
5.
Ca2+ causes vesicles to fuse with
membrane
6.
Neurotransmitter released (exocytosis)
7.
Neurotransmitter binds to postsynaptic
receptors
8.
Opening or closing of postsynaptic
channels
9.
Postsynaptic current excites or inhibits
postsynaptic potential to change
excitability of cell
10.
Retrieval of vesicles from plasma
membrane (endocytosis)
 Transmitter Inactivation:
reuptake and enzymatic breakdown
Reuptake by
transporters
(glial cells)
Reuptake by transporters
Enzymatic
breakdown
Neurotransmitter can be recycled in presynaptic terminal or can
be broken down by enzymes within the cell
NT – Receptor Binding
Receptors are large, dynamic proteins that
exist along and within the cell membrane.
Dynamic – they can increase in number and avidity for
their neurotransmitter according to circumstances.
Two Types of Post synaptic Receptors:
Ionotropic receptors: NT binding results in direct
opening of specific ion channels
Metabotropic receptors: binding of NT initiates a
sequence of internal molecular events which in turn
open specific ion channels
NT binding -> Membrane Potential
Response
Ionotropic Receptors
1.
Work very fast; important role in fast neurotransmission
2.
3.
4.
5.
6.
Each is made of several subunits (together form the complete receptor)
At center of receptors is channel or pore to allow flow of ions
At rest - receptor channels are closed
When neurotransmitter binds -- channel immediately opens
When ligand leaves binding site -- channel quickly closes
Metabotropic Receptors…
1.
Work by activating other proteins called G proteins
2.
3.
4.
Each is made of several transmembrane regions
Stimulate or inhibit the opening of ion channels in the cell membrane
Work more slowly than ionotrophic receptors
Metabotropic Receptors…
1.
2.
Stimulate or inhibit certain effector enzymes
Most effector enzymes controlled by G proteins are involved in synthesis of
second messengers.
*First messenger: ligand.
*Second messenger: effector enzyme
Second messengers: Activate Protein Kinases
Can work by affecting:
NT production, no. synapses formed, sensitivity of receptors,
or expression of genes (long term effects).
Can result in amplification - interconnections.
Other Metabotropic Receptors
1.
Work more slowly than ionotropic receptors
2.
Though it takes longer for postsynapic cell to respond, response is somewhat
longer-lasting
Comprise a single protein subunit, winding back-and-forth through cell
membrane seven times (transmembrane domains)
They do not possess a channel or pore
3.
4.
Tyrosine Kinase Receptors:
TrkA: NGF
TrkB: BDNF and NT-4
TrkC: NT-4
 Receptors superfamilies:
Ionotropic receptors (ligand-gated channels)
Metabotropic receptors (G protein-coupled receptors)
Tyrosine Kinase
Almost all neurotransmitters discovered so far have more than
one kind of receptor -- called receptor subtypes.
Receptors are dynamic
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Large and prolonged intake of certain substances cause an
increase in the number of receptors (basis of withdrawal
response in addiction).
Each NT influences its own receptors independent of the
action of other receptors.
Excitatory and inhibitory NTs.
Post-synaptic neuron sums up the influences of all NTs.
“All or nothing” response (must reach threshold to fire).
Receptors provide for temporal
flexibility (ms to decades)
Multiple types of receptors exist for each major family
of NT receptors.
 Example: serotonin – at least 14 subtypes exist based
on potency of binding to different drugs.
- Imitrix for migraines
- Prozac for depression
Affect different serotonin subtypes.
■ Can develop drugs to target very specific receptors.
■ Provides for much variety and subtlety of response in
the human brain.
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Richard Restak, MD, PhD

“The brain as a whole can be understood as the
summation of billions of interacting neurons
influencing one another via the interplay of
hundreds of neurotransmitters and their
receptors, which in turn influence the passage
of electrically charged particles across the nerve
cell membrane.”
Pharmacology of Synaptic Transmission
Drugs affect synaptic transmission in many different ways.
They can act as agonists or antagonists.
Synapses are targets for many recreational drugs
amphetamine*
phencyclidine
cocaine
nicotine
neurotransmitter
transporters
G protein
coupled receptors
N
neurotransmitter-activated
channels
postsynaptic
cell
G protein-activated
channels
enzymes
C
a
LSD
morphine-heroin
tetrahydrocannabinol
caffeine
?alcohol?
Nicotine
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Nicotine mimics acetylcholine at its receptor site.
Called cholinergic or “nicotinic” receptor.
Especially effective within the areas of the limbic system
involved in the pleasure response.
Prevents transmission of impulses at NM junctions.
Evolved with plants to protect against insects (insecticide).
Banded krait (Malayan snake) kills its
prey by attacking the NM junction
(paralyzes prey).
Nicotine experiment – Keller and Schwartz
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Gave radioactively labeled nicotine to rats.
Found > number of nicotinic
receptors vs. controls.
Unusual – receptors usually ↑ in numbers when
there is a shortage of stimulation.
Solution: nicotine initially exerts a stimulatory
effect (agonist), and then desensitizes receptors to
render them nonfunctional for long periods.
This stimulates the neurons to produce more
receptors.
Nicotine’s Appeal
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Nicotine in the brain causes release
of a wide variety of NTs, including
endorphins, and dopamine (pleasure).
Anxiety-reducing effects.
Lessening of irritation and
aggression, suppression of appetite
(loss of weight).
With repeated smoking, these effects
diminish – the brain becomes tolerant
to nicotine.
Smoker smokes more → dependence.
Nicotine Addiction
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Brain has modified its functioning in
response to regular nicotine “hits”.
Smoker attempts to cut down – craving
due to events at nicotinic-acetylcholine
receptors.
Withdrawal: irritability, frustration, anger, anxiety,
difficulty concentrating, restlessness, decreased
heart rate, increased appetite and/or weight gain.
70-80% of people who try to quit smoking
relapse within one year.
Is nicotine a “bad” drug or a “good”
drug?
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Alzheimer’s disease – dramatically reduced
number of cerebral nicotinic receptors.
Could prescribe nicotine to increase receptors.
Problems: ethical considerations, possible
unknown side effects, much testing to be done.
“At the level of the neuron there are no good or
bad drugs, only drugs that alter the brain.”
Social and economic factors play a role.
Caffeine – “good” or “bad”?
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Caffeine ingestion is almost universal.
Leads to activation of cerebral cortex (EEG).
Most helpful when a person is already tired.
Caffeine blocks the brain’s receptors for
adenosine, an inhibitory NT (inhibits release of
excitatory NTs)
Leads to stimulation, alertness, and an elevation
of mood.
Caffeine – the “bad”
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Too much – restlessness, difficulty composing
thoughts, vertigo, headaches, agitation, and an irregular
heartbeat.
Withdrawal – headache, irritability, restlessness, and
drowsiness.
Headache due to caffeine’s ability to constrict BVs that
feed the brain and scalp.
Withdraw caffeine – vasodilation → headache.
Addicting
Caffeine – the “good”?
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Many over-the-counter headache remedies contain
caffeine.
Caffeine’s actions resemble those of amphetamines –
fatigue disappears, mood improves, and sociability is
enhanced.
It is very likely that new substances will be synthesized in
the future that have similar desirable effects.
Would these developments alter our tendency to put
judgmental labels on commonly used substances that act
on the brain?
“Angel Dust”, a.k.a. PCP
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Phencyclidine was first developed as an anesthetic
– no apparent side effects in animals.
Humans – 15% showed marked confusion,
violence, and psychotic behavior as in
schizophrenia.
Became a popular street drug in the 1960’s.
At the same time, researchers were carrying out
non-FDA approved experiments using PCP as a
“facilitator” for psychotherapy.
Also used as a “model” for schizophrenia.
PCP Side Effects
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Low dose – induced a state resembling drunkenness.
Larger doses – person felt no pain (analgesic effect).
High doses – patient acted schizophrenic – effects
lasted about 4 hours.
Afterwards – depression, paranoia, and sometimes
suicidal or homicidal behavior.
Highest doses – epileptic convulsions, respiratory
depression, and death.
Users found that bad effects could be reduced by
smoking rather than ingesting the drug.
PCP – the “good”
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In 1981, neuroscientists discovered a PCP
receptor in the brain.
Hypothesis: PCP might be acting at the same
sites in the brain responsible for schizophrenia.
Couldn’t confirm or disprove this hypothesis.
However, this lead to many other discoveries
that revolutionized treatment for stroke and
other destructive brain injuries (excitotoxic
theory – glutamate).
Synapses are the targets of
therapeutic drugs
• Antidepressant drugs
serotonin uptake inhibitors
• Analgesics (morphine)
opiate receptor agonists
• Antipsychotic drugs
DA receptor antagonists
• Anticonvulsant drugs
GABAA modulators
• Antianxiety agents
GABAA modulators