Transcript Neurotransmitters PPT

Physiology of a Neuron
From Dendrite to synaptic
transmission
1
NOTE ABOUT THIS LECTURE
• This is a long, tough lecture at the end of the
course, so you will be tested on it in
segments:
• Quiz 9 (slides 1-51)
• Lecture exam 4 (slides 1-64)
• The section at the end on Drugs and Toxins
(slides 65-83) will not be tested in this A&P
201 course. It will be on the first lecture exam
of A&P 202.
Neuron Anatomy
Soma (cell body)
Axon (transmits signals)
Axon hillock
(trigger zone)
Dendrites (receive signal)
Synaptic knob
(stimulates
another cell)
•Draw and label a neuron
–Dendrite - projections from the soma
•the sensory portion of the neuron
–Soma - main body of the neuron
–Axon hillock- trigger zone
–Axon - extends from soma to the knob
•the effector part of the neuron
–Terminal bouton/synaptic knob
–Synaptic vesicles
–Synaptic cleft
Function of Dendrites in Stimulating Neurons
• Dendrites are spaced in all directions
from the neuronal soma.
– allows signal reception from a large
spatial area providing the opportunity
for summation of signals from many
presynaptic neurons
• Dendrites transmit signals after the
opening of LGC’s
• LGC (Ligand-gated channels): these
open when a ligand (neurotransmitter)
binds to them. They do not need an
action potential to open them.
– LGC’s have receptors for
neurotransmitters
– LGC’s are located on dendrites
Axon
hillock
LGC’s
VGC’s
4
Types of Ligand Gated Channels (LGC’s)
Many human diseases are associated with dysfunction
of particular types of ion channels.
Some Amino Acids have positive charges which repel
ions with a positive charge. Some AA’s have negative
charges. Amino acids on LGC’s therefore control ion
selectivity (what ions may pass). Sodium (Na+) has its
own LGC. So does potassium (K+) and Cloride (Cl-).
Na+ LGC
K+ LGC
-74 mV
0
mV
What would happen to the
resting membrane potential if
these channels opened?
Cl- LGC
• The Excitatory Postsynaptic Potential (EPSP)
– Postsynaptic refers to the dendrite of the neuron receiving the signal.
– The neurotransmitter binds to its LCG, which opens a Na+ ionophore. Na+ ions then rush
to the inside of the cell membrane. They take their positive charge with them, so the
inside of the cell membrane is now more positively charged than it was.
– This increase in voltage above the normal resting potential (to a less negative value) is
called the excitatory postsynaptic potential.
– How many mV do we need to reach threshold? If Resting Membrane Potential is minus
74, we need to get above zero to start an action potential.
dendrite
Membrane is somewhat depolarized,
more likely to reach threshold soon.
-74 plus +60 = -14 mV
+60 mV
Na+: 20 mEq/L
axon
-14mV
6
• The Inhibitory Postsynaptic Potential (IPSP)
– Inhibitory synapses open K+ or Cl- channels.
– When a K+ channel opens, K+ rushes OUT of the cell, taking its
positive charges with it. The inside of the cell membrane becomes
MORE NEGATIVE.
– When a Cl- channel opens, Cl- rushes INTO the cell, taking its
negative charges with it. The inside of the cell membrane becomes
MORE NEGATIVE. Both K+ and Cl- cause hyperpolarization of the
neuron, making the neuron LESS likely to reach threshold.
Losing +20 or gaining -8 mV will both
-74 plus 20
-94 mV of the charge
increase
the=negativity
inside the cell (hyperpolarization),
making
likely
-74 plusit 8less
= -82
mVto reach threshold.
K+ : 4.5 mEq/L
Cl- : 107 mEq/L
20 mV
8 mV
axon
7
Whether a neuron “responds” or not,
depends on temporal and spatial summation
of EPSPs and IPSPs
These channels open and close rapidly providing a
means for rapid activation or rapid inhibition of
postsynaptic neurons.
There might be EPSP’s firing at the same time as
IPSP’s. Add up all the charges from the excitatory and
inhibitory potentials to see which one wins!
Temporal summation: same presynaptic neuron fires repeatedly
Spatial summation: additional presynaptic neurons fire
8
Spatial summation- stimuli from two
different presynaptic neurons (different
locations)
9
Stimulating an Excitable Cell
• Electrical stimulation (or even
mechanical stimulation) can
result in changes in voltage.
• Depolarizing currents change
the voltage on the membrane,
bringing it toward threshold:
–If stimuli are threshold or
above threshold stimuli, the
result is an action potential
Excitatory and inhibitory neurons
release their NT at the same time
on the same neuron. The
postsynaptic neuron has to
summarize the input of positive
and negative charges. If the
overall effect is positive enough,
an action potential will begin.
People with Parkinson’s
disease have a problem
coordinating the excitatory
and inhibitory actions of their
skeletal muscles. They have
trouble starting and stopping any
motion, and they shake at rest.
10
What happens at threshold?
•
•
•
•
•
•
•
At threshold, there is a temporary, short-lived membrane permeability change.
The cell membrane becomes 40 x more permeable to Na+ and then quickly
returns to previous state.
How? By the opening and closing of voltage-gated channels (VGC).
Both VGCs and LGC’s allow Na+ into the cell. LGC’s do this when a ligand
(neurotransmitter) binds to the cell membrane. VGC’s do this when the
voltage of the cell membrane goes from negative to positive.
The VGC’s which are inhibitory of an action potential are those that open K+
and Cl- channels. These ions both increase the negative voltage of the cell
membrane, making farther away from starting an action potential.
The VGC’s that are excitatory are those that open Na+ or Ca++ channels. Both
of these ions increase the positive voltage of the cell membrane. If the charge
is enough to go from negative 74 mV to zero (threshold) or to a positive
voltage, an action potential will be launched.
LGC’s are on dendrites only.
VGC’s are on the axon, starting at the hillock and continuing to the synaptic
knob.
11
12
Ion channels
Activation, Inactivation, deactivation
closed
• Depolarization causes:

Deactivation:
Closed
Na+ channels to activate
(open)
but it also causes inactivation


inactivated channels do
not pass any ions (nonconducting state)
By contrast, most K+
channels show activation
and deactivation but not
inactivation
inactivation
open
inactivated
Activation:
Open and
working
Inactivation:
Open and not
working
13
Copyright © 2006 by Elsevier, Inc.
Refractory Periods
mV
0
-40
Threshold
-80
0
1
Absolute
2
3
4
5 msec
Relative
Because Na+ channels have an inactive phase, it causes a refractory period,
which prevents a new action potential from starting right away.
Refractory periods limit maximum frequency of action potentials (Aps)
14
Functions of action potentials
• Information delivery to CNS
 Transfers all sensory input to CNS.
 Amplitude of the AP (how strong the AP is) does not change, but the
frequency of APs varies. The frequency pattern is a code (like Morse
Code) that transmits information about the stimulus (light, sound,
taste, smell, touch) to the brain.
• Rapid transmission over distance (nerve cell APs)
 Neurons can rapidly fire thousands of times without depleting the
sodium gradient.
 Note: speed of the Action Potential depends on the size of the neuron
fiber and whether or not its axon is myelinated.
 The larger the neuron, the less resistance there is, so it is faster. The
more lanes on the freeway, the faster you get home. Myelinated
axons are also faster than unmyelinated.
 In non-nervous tissue, action potentials initiate a response.
 Muscle  contraction
 Gland  secretion
15
Figure 5-17; Guyton & Hall
The AP is a passive event: ions diffuse down their EC gradients when
gated channels open.
A “wave of depolarization” occurs along the neighboring areas.
Occurs in one direction along the axon; actually, AP regenerates
over and over, at each point by diffusion of incoming Na+ ….WHY?
Refractory period (Na+ channels become inactivated).
Saltatory Conduction
 This type of conduction is found with myelinated axons.
 AP’s only occur at the nodes (Na channels concentrated here!)
 increased velocity
http://www.blackwellpublishing.com/
 energy conservation
matthews/actionp.html
16
Conduction velocity
- non-myelinated vs myelinated -
non-myelinated
myelinated
A neuron with myelin saves on ATP.
A child under three should not be on a low fat diet because a lot of
their myelin is being made during that time.
17
Multiple Sclerosis
- MS is an autoimmune
disorder where the body’s
WBC’s destroy the myelin
sheaths.
- About 1 person per 1000 in
US is thought to have the
disease - The female-to-male
ratio is 2:1 - whites of northern
European descent have the
highest incidence
http://www.emedicine.com/pmr/topic82.htm
Copyright © 2006 by Elsevier, Inc.
Patients have a difficult time describing
their symptoms. Symptoms are bizarre
and unrelated. Patients may present
with paresthesias (tingling sensation)
of a hand that resolves, followed in a
couple of months by weakness in a leg
or visual disturbances. Patients
frequently do not bring these
complaints to their doctors because
they resolve. Eventually, the resolution
of the neurologic deficits is incomplete
or their occurrence is too frequent, and
18
the diagnosis of MS begins.
• Structures important to the
function of the synapse:
– presynaptic vesicles
• contain neurotransmitter substances
to excite or inhibit postsynaptic
neuron
The Synapse
– mitochondria
• provide energy to synthesize
neurotransmitter
• Membrane depolarization by an
action potential causes emptying
of a small number of vesicles into
the synaptic cleft
• Presynaptic membranes contain
voltage - gated calcium channels.
Voltage Gated
Calcium Channel
– depolarization of the presynaptic
membrane by an action potential
opens Ca2+ channels
Ca+2
2+
– influx of Ca induces the release of
the neurotransmitter substance
•Postsynaptic membrane contains receptor proteins for the
transmitter released from the presynaptic terminal.
19
•
•
•
Presynaptic neuron, axon:
The VGCs allow Na+ to enter the inside of
the cell membrane, then Na+ leaves again,
and the AP is propagated (carried) down the
length of the axon.
Presynaptic neuron, terminal knob:
There are no more VGC’s for Na+. The
VGC’s are now for Ca++. They let Ca++
into the interior of the cell. The Ca++
causes the vesicles in the knob to move
towards the cleft and release their contents
(the neurotransmitters) into the synaptic
cleft.
Postsynaptic neuron, dendrite:
The cell membrane on the dendrite contains
proteins called LGC’s. The neurotransmitter
attaches to them. This causes nearby VGC’s
to open. If the VGC is excitatory, a new AP
begins in the postsynaptic cell. If the VGC
is inhibitory, the AP will stop.
Voltage Gated
Sodium Channels
(from dendrites to end of axon)
Voltage Gated
Calcium Channels
NT
Calcium
In the meantime, an enzyme arrives at the
synaptic cleft and deactivates the
neurotransmitter. The mitochondria make
more neurotransmitters (NT) and store
them in new vesicles.
Ligand Gated Channels:
Bind to NT and open nearby VGC’s
20
Synaptic Events -watch animation
• Neurotransmitters (NT) are
released and diffuse across
synaptic cleft
• NT bind to receptors (LGC’s)
on the post-synaptic cell
• The LGC opens, and ions
diffuse in or out, depending on
which LGC it is
• The change in voltage causes
depolarization or
hyperpolarization
• If depolarizing, called EPSP
• If hyperpolarizing, called IPSP
21
NEUROTRANSMITTERS
AND
NEUROTRANSMITTER
RECEPTORS
We’re talking about signals and what
they mean to a neuron! What
happens if we block signals?
22
NEUROTRANSMITTERS
GENERAL SEQUENCE OF EVENTS AT
CHEMICAL SYNAPSES
• NT synthesis and storage in
presynaptic cell
• NT release by exocytosis
(Ca++ triggered event)
• Diffusion across cleft
• NT reversibly binds to
receptors (LGC) and opens
gates, allowing ion diffusion
• NT removal from synapse
(destruction, diffusion away)
• NT reuptake by presynaptic
cell for recycling
VOCC
24
NTS ACTION
• NT diffuses across synaptic cleft to bind to
receptor (LGC) on postsynaptic
membrane
• Can generate an electric signal there
(EPSP’s or IPSP’s)
• These are graded potentials (the more
channels there are, the more the charge
changes)
• Effect depends which ions are allowed to
diffuse across membrane, how many
and for how long. Effect depends on the
selectivity of the channel.
• What if the LGC are…..
• Na+ selective
• K+ selective
• Cl- selective
• What happens to the voltage on the
postsynaptic cell? Is it an EPSP or an
IPSP?
25
NEUROTRANSMITTERS (NTS)
• NTs are present within the
presynaptic neuron
• They are released in response to
presynaptic depolarization,
which requires calcium
• Specific receptors must be
present on the postsynaptic cell
• NT must be removed to allow
another cycle of NT release,
binding and signal transmission
• Removal: reuptake by
presynaptic nerve or
degradation by specific enzymes
or a combination of these
26
SYMPATHETIC AND
PARASYMPATHETIC NERVOUS SYSTEM
•
•
•
•
Sympathetic Neurons
Increased heart rate and blood pressure
Decreased food digestion
“Fight or Flight”
•
•
•
•
Parasympathetic Neurons
Decreased heart rate and blood pressure
Increased food digestion
“Rest and Digest”
Notice that the heart is innervated by both sympathetic and
parasympathetic neurons….
SYMPATHETIC AND
PARASYMPATHETIC NEURONS
• If an organ is dually innervated by sympathetic and
parasympathetic nerves, how will the organ know if
sympathetic or parasympathetic is barking louder?
The receptors that have the most transmitter bound
will cause the biggest result.
• The heart has receptors that allow both para and
sym to have effects. A lot of organs are dually
innervated so they can adjust their physiology.
• Furthermore, a sympathetic neuron can cause
excitation in one organ and inhibition in another
organ. A parasympathetic neuron can also cause
excitation in one organ and inhibition in another
organ.
SYMPATHETIC AND
PARASYMPATHETIC NEURONS
• There are two faucets in your bathroom, turn both on halfway, and water is
lukewarm. To make it hot, either turn up hot water or turn down cold water, or
both. If we suppress the parasympathetic system (cold water), the
sympathetic system (hot water) will gain more control. If you stimulate the
parasympathetic system, it will gain control. Parasympathetic and
sympathetic neurons both fire onto the same organ at the same time. The
question is when does the sympathetic system have more control? When
does the parasympathetic system have more control?
• If a particular drug mimics the parasympathetic system, then the
parasympathetic system has more control. What effect does that have? The
heart rate will be slower. If sympathetic is stronger, how will body act? Heart
rate increases.
• We can completely shut down parasympathetic and rev up sympathetic. In
an ER show, when the patient’s heart stops, they get the epinephrine and get
the atropine. The epinephrine is stimulating the sympathetic system and the
atropine is blocking the parasympathetic system (shutting off the antagonist).
HEART TRANSPLANT PROBLEM
• When you take out a heart, the nerves that innervate the heart are cut out too.
There is no way to suture back the nerves when you put in a new heart.
• The new heart will have a faster heart rate because cardiac cells like to beat
fast. The parasympathetic neurons cause the heart rate to slow, but they are
now cut.
• The post-op patient cannot allow themselves to become overly anxious, angry,
or sexually aroused after heart transplant.
• When they have those emotions, the sympathetic system can still release
epinephrine because it is a hormone, not a nerve. Epinephrine is made by
adrenal glands and circulates in the blood. However, the patient no longer has
parasympathetic neurons attached to the heart to counter the effects of
epinephrine.
• It will therefore take them a long time to calm down from the effects of
epinephrine due to anger, anxiety, etc) because they have to wait for the
epinephrine to be metabolized. There are no parasympathetic hormones to
calm you down.
• How can we use the parasympathetic system to make the heart cells less
active? Use a medicine to open the potassium channels, making the inside of
the cell more negative (hyperpolarized). The number one way HR is regulated
is by potassium.
CLASSIFICATION OF NTS
• Chemical Classification
• Large Molecule
• Peptides
• Small Molecule
• Adrenergic
• Catecholamines
• Cholinergic
• Dopaminergic
• Serotonergic
• Amino Acid NT’s
• Functional Classification
• Metabotropic
• Ionotropic
CHEMICAL CLASSIFICATION
1) Small Molecule NTs
• Acetylcholine (ACh)
• Catecholamines
• Amino Acid Neurotransmitters
• 2) Large Molecule (Peptide) NTs
• ADH (vasopression); increases blood volume
• Angiotensin; vasoconstriction (raises BP)
• Bradykinin; vasodilation (lowers BP)
We will talk about large molecule NTs in later lectures.
This lecture will focus on small molecule NTs.
SMALL MOLECULE
NEUROTRANSMITTERS
• Cholinergic
• Acetylcholine (ACh)
• mACh
• nACh
• Amino Acid NTs
• Glutamate
• GABA (inhibitory)
• Glycine (inhibitory)
CATECHOLAMINES
Adrenergic catecholamines:
• Norepinephrine
• Epinephrine
Dopaminergic catecholamine:
• Dopamine
Serotonergic catecholamine:
• Serotonin
Neurons that make epinephrine or norepinephrine are called Adrenergic neurons
Neurons that make dopamine are called Dopaminergic neurons
Neurons that make serotonin are called Serotonergic neurons
33
ACETYLCHOLINE (ACH)
• Neurons that use this NT
are called cholinergic
neurons.
• All skeletal muscle is
innervated by cholinergic
neurons.
• Also used by sympathetic
and parasympathetic
neurons
• Ach is removed from the
synaptic cleft by the
enzyme Acetylcholine
esterase (AChE)
34
GLUTAMATE
• Very important in CNS
• Nearly all excitatory
neurons use it
• Too much glutamate
causes excitotoxicity
due to unregulated
calcium influx
• Antagonists to
Glutamate receptor
help stop neuronal
death after stroke
• Too little glutamate
leads to psychosis
(delusional, paranoid,
lack of contact with
reality)
35
GLUTAMATE
• Dangerous: someone with stroke or trauma releases a lot of
NTs, causes damage to undamaged neurons, The healthy
neurons are being over stimulated, too much calcium, causes
cytotoxicity. Too much NT can kill the cell.
• Only 10% of people with Parkinson’s and Alzheimer’s are
caused by bad genes; the rest are caused by calcium
dyshomeostasis (The calcium is not being monitored properly
in the body).
• Those who have stroke are given a glutamate antagonist to
protect them.
• If you don’t have enough glutamate, inhibitory NTs will gain
momentum.
• Too little glutamate leads to psychosis, perceives reality
differently than normal.
GABA
AND
• Major inhibitory
neurotransmitter in CNS
 Decreased GABA causes
seizures
 Anticonvulsants target
GABA receptors or act as
GABA agonists
 Benzodiazepines (valium)
and ethanol (drinking
alcohol) both trigger GABA
receptors……use
benzodiazepines during
alcohol detox.
GLYCINE
• Glycine- also inhibitory
• Mostly in spinal cord and
brainstem motor neurons
http://pharma1.med.osaka-u.ac.jp/textbook/Anticonvulsants/GABA-syp.jpg
37
GABA
• Alcohol stimulates GABA receptors, so you are
causing IPSPs, reflexes slow down, reach
threshold less quickly. They have to work at
overcome their lazy tongue to get words out.
• When they try to stop drinking all at once, the
excitatory NTs gain control, and they get
tremors and visual overstimulation. Need
benzodiazepam (valium) while weaning off the
alcohol.
• GABA agonists (drugs that act like GABA, such
as anti-convulsants) can also be given.
GABA
• Benzodiazepines (such as valium) enhance the
effect of gamma-aminobutyric acid (GABA), which
results in sedative, hypnotic (sleep-inducing),
anxiolytic (anti-anxiety), anticonvulsant, muscle
relaxant and amnesic action.
• These properties make benzodiazepines useful in
treating anxiety, insomnia, agitation, seizures,
muscle spasms, alcohol withdrawal and as a
premedication for medical or dental procedures.
CATECHOLAMINES
• These are released by adrenal glands in response to stress; they are
part of the sympathetic nervous system (fight or flight). They circulate
in the bloodstream.
• Removed by reuptake into terminals via sodium dependent transporter
• Mono-amine oxidase (MAO) is an enzyme that degrades
catecholamines. Therefore, an MAO inhibitor will allow catecholamines
to excite the nervous system.
• Anti-anxiety and anti-depression medicines are MAO-inhibitors
• DO NOT MIX SYMPATHOMIMETIC (those that imitate catecholamines)
WITH MAO INHIBITORS. It doubles the excitatory effect in the nervous
system and can be deadly.
• Examples of Sympathomimetic are medicines for cardiac arrest, low
blood pressure, and some meds that delay premature labor.
• MAO inhibitors plus sympathomimetics allow the excitatory effect of
fight-or-flight to continue to excess, and the person’s blood pressure
goes up to a crisis level.
• In other words, don’t mix anti-depressant meds with meds for cardiac
arrest, low blood pressure, and some meds that delay premature labor.
40
CATECHOLAMINES
• Epinephrine (“above the kidney”)
• Epinephrine is secreted by the adrenal gland, which sits above
the kidney.
• It’s action is excitatory (fight or flight)
• Norepinephrine
• Norepinephrine is secreted by neurons from CNS and by
neurons in sympathetic ganglia
• Its action is mainly excitatory, can be inhibitory.
• Dopamine
• Secreted by neurons in CNS
• Its action is inhibitory
• Epi and norepi are made from dopamine
• Serotonin
• Secreted by neurons in the CNS
• Its action is mainly excitatory. It can excite one cell but inhibit
another.
DOPAMINE
• Parkinson’s Disease
(Parkinsonism)
• Loss of dopamine from
neurons in substantia
nigra of midbrain
• Resting tremor, “pill
rolling”, bradykinesia
(slow walking) gait
• Treat with L-dopa.
(Crosses BBB) or MAO
inhibitors
• Side effects
(hallucinations, motor
problems)
The Case of the Frozen Addicts,
by Langston, J. W
42
BRAIN REGIONS
• The motor cortex is the region of the brain that contains the
neurons that move the muscles of the skeleton.
• The basal nuclei region of the brain (between the corpus
callosum and thalamus) inhibits some motor neurons so that
unwanted body movements do not occur. The basal nuclei
regulate stopping, starting, and coordination of movements.
The basal nuclei are inhibitors of movement. They are like strict
parents that tie their kids up to keep them from doing wild
things.
• The substantia nigra region of the brain secretes dopamine,
which inhibits the basal nuclei (it inhibits the inhibitor). Thus, the
excitatory neurons can make the body move. The substantia
nigra and Dopamine are like the bosses who demand that the
parents (basal nuclei) leave town for a business trip. With the
inhibitor gone, the kids throw a house party.
BRAIN REGIONS
• If the substantia nigra (the boss) is damaged (no more
dopamine), the basal nuclei (the parents) are no longer
inhibited. So the parents stay home and tie the kids up to keep
them from moving their bodies. This is the problem in
Parkinson’s disease.
• If the basal nuclei (the parents) are damaged (the parents are
out of town), the patient will have excessive movement. This is
Huntington’s disease.
• Thus, there are two ways the basal nuclei (the parents) can be
a problem: either the basal nuclei themselves are
dysfunctional (not enough inhibition of movement; the
parents leave town and the kids throw a party; Huntington’s
disease), or the dopamine levels (the boss) are too low (the
boss is sick so he does not make the parents leave on a
business trip, so the kids are tied up; Parkinson’s disease).
PARKINSON’S DISEASE
• Parkinson’s Disease is a problem in the substantia nigra region
of the midbrain; that area secretes dopamine.
• People with Parkinson’s disease lack dopamine (the boss), so
the basal nuclei (the parents) inhibit body movements.
• Therefore, the patient has trouble initiating body movements.
They also develop a “pill rolling” tremor at rest.
• Parkinson’s Disease symptoms are the opposite of Huntington’s
disease.
• Parkinson’s Disease patients cannot initiate movements.
• Huntington Disease patients have sudden, jerky movements.
HUNTINGTON’S DISEASE
• Huntington’s disease: rapid, jerky motions.
• Since the basal nuclei are damaged, the inhibition
of the motor cortex is removed, so excitatory
neurons go unchecked, and the person has sudden
jerky movements. Their body writhes around like
they are dancing (chorea).
• Other symptoms include cognitive decline and
psychiatric problems.
• Huntington’s disease is hereditary (50% chance of
each child getting it if one parent has it).
• Age of onset is usually 35-45 years of age, so
symptoms do not manifest until after they have
children and pass on the bad gene.
DOPAMINE
• Using too much of the drug “Meth” will kill Dopaminergic neurons,
causing Parkinson’s symptoms.
• Dopamine is used in the substantia nigra portion of the midbrain
where excitatory and inhibitory neurons need to integrate.
• If you lose excitatory neurons, you will gain inhibitory stimulus.
• Parkinson’s patients have problems starting movements, and
coordinating the excitatory/inhibitory stimulus to muscles while
walking. Stopping motions is also hard. They need a trained dog
to pull them up from a seated position and help them to take the
first step, and to stop them when they want to stop.
• Treatment is an MAO inhibitor or L-dopa, which can cross BBB,
unlike dopamine. Cells can convert L-dopa to the required
dopamine earlier on in the disease, but as cells die later, they
cannot perform this conversion.
• Stem cells can be injected to cause the remaining neurons to
replicate and help them get more control.
SEROTONIN
• Synthesized from
tryptophan
• Serotonin reuptake
inhibitors are antidepressant drugs
• Ecstasy causes more
release!
• Mood elevator, “feelgood” neurotransmitter
48
SEROTONIN
• At certain times of the day you get your
serotonin surge. Some are morning people,
some are night people.
• If you take an SSR inhibitor, it helps serotonin to
stay in cleft longer, feel good longer.
• These types of drug are prescribed for
depression.
• The street drug, Ecstasy, mimics serotonin. If you
meet someone while taking Ecstasy, you will fall
in love. Better wait six months for it to clear out
your system before you marry them!
DISORDER OF PHENYLALANINE METABOLISM
PHENYLKETONURIA (PKU)
• Catecholamines (such as epinephrine) are
derived from the amino acid tyrosine.
• PKU is a genetic, autosomal recessive
disorder (1:20,000 births)
• Lack of enzyme phenylalanine hydroxylase
• Inability to convert phenylalanine (aa) from
the diet to tyrosine (aa)
• Without this enzyme, waste products
(ketones) build up in the blood and are
toxic to neurons. The ketones are spilled in
the urine as well. Symptoms are seizures,
poor motor development and mental
retardation in a developing child.
phenylalanine
Phenylalanine
hydroxylase
Tyrosine
Phenylalanine  TYROSINE  L-DOPA  dopamine  norepinephrine  epinephrine
DISORDER OF PHENYLALANINE METABOLISM
PHENYLKETONURIA (PKU)
• Routine testing at birth by heel stick blood sample
• Prevented by dietary restriction of phenylalanine.
• No whole protein during childhood, while nervous system is
developing (until age 20).
• After that, the person can go off the diet, but the ketones will
begin to accumulate. When they start to feel sluggish, and
can’t finish a task on time, they need to go back on the diet for
a while.
• A woman must stay on the diet during pregnancy or the
ketones will cross the placental and kill the neurons of her baby.
• Artificial sweeteners such as Sweet N Low, and diet sodas are
high in phenylalanine, and must be avoided in PKU patients.
• This genetic condition is more likely to occur if you have a child
with your first cousin (or closer relative)
RECEPTORS
FOR NEUROTRANSMITTERS
RECEPTORS FOR NTS
•
•
•
•
•
Two Types of ACh Receptors
Muscarinic ACh receptors
Nicotinic ACh receptors
Two Types of Adrenergic Receptors
Alpha adrenergic receptors
• Alpha 1 receptors
• Alpha 2 receptors
• Beta adrenergic receptors
• Beta 1 receptors
• Beta 2 receptors
• There are also receptors for amino acid NTs
ACH RECEPTORS
• Muscarinic ACh receptors (mAChR)
• more sensitive to muscarine than to nicotine
• Muscarinic substances activate the parasympathetic
nervous system (rest and digest). Increased saliva, tears,
diarrhea.
• Antidote for overdose is atropine.
• They use G-proteins to activate a nearby ion channel
• Nicotinic ACh receptors (nAChR)
• more sensitive to nicotine than to muscarine
• They do not use G-proteins; they open ion channels directly
• Both Muscarinic and nicotinic receptors are found on
skeletal muscle, which contract when ACh binds there.
WHAT NEURONS SECRETE ACH?
• All preganglionic neurons (sympathetic and
parasympathetic) and postganglionic
parasympathetic neurons secrete Ach, so they use
muscarinic and nicotinic receptors.
• About 98% of postganglionic sympathetic neurons
secrete epi or norepi, but 2% of postganglionic
sympathetic neurons secrete Ach (those that supply
the sweat glands), so those are the ones that would
use muscarinic receptors as well. The sympathetic
system only uses nicotinic receptors for the preganglionic neurons.
AFFECTS OF NICOTINE
• Acts as a stimulant: increases dopamine (in the
reward center of the brain), which causes euphoria
and relaxation, and it is addictive.
• Nicotine has a higher affinity for acetylcholine
receptors in the brain than those in skeletal muscle.
• Tobacco smoke contains MAO inhibitors . MAO
enzymes break down dopamine, norepinephrine,
and serotonin. Smoking prevents the breakdown of
these neurotransmitters.
• This contributes to the addictive properties of
tobacco.
ADRENERGIC RECEPTORS
• Alpha adrenergic receptors
• Alpha 1 receptors
• Causes vasoconstriction
• increases blood pressure
• Decreases GI motility
• Alpha 2 receptors
• Causes vasodilatation
• decreases blood pressure
• Decreases GI motility
• Beta adrenergic receptors
• Beta 1 receptors
• Increases heart rate
• Increases cardiac output
• Beta 2 receptors
• Causes vasodilatation
• Decreases blood pressure
• Opens bronchioles
• Decreases GI motility
All of these receptors use G-Protein (describes
the functional classification of receptors)
FUNCTIONAL CLASSIFICATION OF
RECEPTORS BASED ON THE TYPES OF
LIGAND GATED CHANNELS
• Ionotropic receptors bind to a NT and have a
channel that extends into cell. They are the
receptor and the transporter
• Metabotropic receptors need a series of enzymatic
actions to change a gated channel somewhere
else. The binding of the NT outside of the cell
activates a G-protein on the inside of the cell which
breaks apart into two pieces. One of those pieces
goes somewhere else in the membrane to open up
another channel.
Ionotropic
Metabotropic
59
IONOTROPIC RECEPTORS
Nicotinic AChR
Serotonin
Glutamate
GABA
Glycine
60
Metabotropic Receptors
RECEPTORS WHICH ARE METABOTROPIC
Muscarinic Acetylcholine receptors
Alpha and Beta-Adrenergic receptors
Dopaminergic receptors
61
G-PROTEINS
• When the G-Protein is activated, it breaks into two
pieces. One of the pieces is called the second
messenger, which is the part that opens the nearby
ion channel.
• It also activates other enzymes inside the cell which
may cause various changes.
• These changes include activation of gene
transcription (to form new proteins, changing the
metabolism; used especially in making new
memories )
SEQUENCE OF EVENTS OF A
METABOTROPIC RECEPTOR
• Step 1: NT binds to receptor
• Ach binds to muscarinic receptors
• Norepi and epi bind to adrenergic receptors
• Step 2: The G proteins activate
• The G-protein (used by both muscarinic and adrenergic receptors) is found
inside every cell of the body. There are different types of G proteins; either GS
(stimulating G protein) or GI (inhibiting G protein). GS means the G protein will
lead to events that lead to an increase in activity in the cell. We will only focus
on these. You will hear about the GI proteins in pharmacology.
• Step 3: Second messenger activates another protein called the late effector
protein
• G-Proteins of sympathetic s neurons activate protein kinase A
• G-Proteins of parasympathetic s neurons activate protein kinase B
• We ultimately want kinase activity, which phosphorylates (puts a phosphate
molecule on) other proteins in a cell. This changes the activity level of the cell.
Small Molecule Neurotransmitters
• Acetylcholine (ACh)
– mACh (“cholinergic”)
– nACh (“cholinergic”)
• Amino Acid NTs
– Glutamate
– GABA (inhibitory)
– Glycine (inhibitory)
Catecholamines
Adrenergic catecholamines:
• Norepinephrine
• Epinephrine
Dopaminergic catecholamine:
• Dopamine
Serotonergic catecholamine:
• Serotonin
IONOTROPIC RECEPTORS ARE IN RED
METABOTROPIC RECEPTORS ARE IN BLACK
64
METABOTROPIC RECEPTORS
• There are two types of metabotropic receptors:
• muscarinic acetylcholine (mostly used by
parasympathetic neurons)
• adrenergic receptors (mostly used by sympathetic
neurons)
GO HOME AND PONDER THIS:
• Sympathetic neurons that secrete ACh use muscarinic receptors.
• Sympathetic neurons that secrete epinephrine primarily use adrenergic
receptors (metabotropic)
• Parasympathetic neurons that secrete epinephrine use adrenergic receptors
(also metabotropic).
• Therefore, both sympathetic and parasympathetic use metabotropic
receptors.
• Sympathetic neurons try to speed up the heart rate. They will stimulate
adrenergic (alpha and beta) receptors (norepinephrine), and will also bind G
protein (metabotropic).
• Parasympathetic neurons try to slow the heart rate. They will stimulate
muscarinic receptors (ACh), and will bind G protein (metabotropic).
DRUGS AND TOXINS
Spastic paralysis vs. flaccid paralysis
67
SPASTIC VS. FLACCID PARALYSIS
• Flaccid paralysis is when the muscle cannot
contract at all. The muscle stays weak and floppy.
• Spastic paralysis is when the muscle stays in
contraction. You still cannot move the muscle
properly, but in this case, the muscle is too rigid.
SODIUM VGC BLOCKERS
• Lidocaine- used as
local anesthesia
• Tetrodotoxin-puffer
fish and newts (TTX)
• Saxitoxin- caused
by red tide; a type
of red algae called
dinoflagellates
accumulates in
shellfish (SXT)
• Causes flaccid
paralysis
69
SODIUM VGC BLOCKERS
• Na+ VGC blockers will block the sodium channel,
so you can’t have AP at all. Get flaccid paralysis.
• When preparing a puffer fish for food, if the chef
makes one nick in its liver, it will contaminate the
whole meat with TTX toxin, which paralyzes the
diaphragm.
• Salamanders and newts have this toxin as well.
Sometimes the toxins can get through the skin just
by handling them; get tingling. Don’t lick a
salamander!
VESICLE BLOCKERS
• Clostridium botulinum:
• Bacterium that has a protease
(enzyme that breaks down proteins)
called botulism. Botulinum breaks
down the docking proteins that
anchor vesicles to the cell membrane)
• Inhibits ACh neurotransmitter release;
muscles can’t contract.
• Botulism is found in undercooked
turkey and dented cans of food. If
ingested orally, will paralyze the
diaphragm; die of suffocation.
• It causes flaccid paralysis
• It is the muscle killer in “BOTOX”
injections. The muscles die so the
wrinkle lines relax. These small facial
muscles can grow back in three
months; need another shot. It is also
used for migraines.
71
MACH-R BLOCKER/ COMPETITOR
• Atropine
• Flaccid paralysis
• Smooth muscle,
heart, and glands
72
MACH-R BLOCKER/ COMPETITOR
• These block the parasympathetic system, so the
sympathetic gets more control.
• Blocking the parasympathetic neurons will cause
flaccid paralysis in the intestines.
• If heart has stopped, inject atropine to block mACH
receptors on cardiac muscles, and heart rate will
increase.
MACH-R BLOCKER/ COMPETITOR
• Your iris has smooth muscle. If we block Ach, the
muscles will pull, opening pupil.
• Opium derivatives block muscarinic Ach receptors,
causes dilated pupils.
• Chemical warfare drugs that stimulate the
muscarinic Ach receptors causes the
parasympathetic system to gain more control;
increase gut motility, sweat, diarrhea, salivation. A
type of mushroom does this, too, and it can kill you.
NACH-R BLOCKER/ COMPETITOR
• Curare
• From tree sap
• Causes flaccid
paralysis
• Large dose:
asphyxiation
75
NACH-R BLOCKER/ COMPETITOR
• South American Indians use curare as a poison on
the tips of arrows. Injecting it into the bloodstream
causes death of the animal. However, the digestive
system can deactivate it, so it is safe to eat an
animal that was killed with curare. How does it kill?
• Nicotinic Ach receptors (nACH-R) are mainly found
in skeletal muscle. If you block them with curare,
you block the ability for ionotropic receptors to
open, so Na+ cannot move in. That blocks
excitation, so muscle will not contract, and you get
flaccid paralysis.
ACHE (ACETYLCHOLINE ESTERASE)
BLOCKERS
• Neostigmine
• Physostigmine
• Spastic paralysis
• These drugs are
used to treat
Myasthenia Gravis,
an autoimmune
disease that causes
ptosis (droopy
eyelid)
77
MYASTHENIA GRAVIS
• Myasthenia Gravis (autoimmune disorder). The
body’s antibodies attacks the nicotinic Ach
receptors, so there are fewer of them, less Na+
coming in, fewer action potentials.
• Symptoms usually begin in the eyelid and facial
muscles, and manifests as drooping muscles on half
or both sides of the face, drooping eyelids, and
slurred speech.
• Their eyelid muscles are often the first muscles to
become fatigued.
• To test for this, force open the eyelids, have them
look up, and will quickly cause fatigue, and their lids
will droop (ptosis).
MYASTHENIA GRAVIS
• Treatment is to give a medicine to inhibit ACh-ase.
• That way, the ACh will not be deactivated and it can stay
around longer to keep muscles contracting. Too much will
cause spastic paralysis.
• Neostigmine is an anti-cholinesterase drug which reduces the
symptoms by inhibiting Ach-ase activity, preventing the
breakdown of Ach. Consequently, Ach levels in the synapse
remain elevated, so Ach is available to bind to those few
functional Ach receptors that are left.
• Neostigmine is reversible, so you need to keep taking it daily. It is
therefore useful as a medicine.
ACETYLCHOLINE ANTAGONISTS
• Some INSECTICIDES inhibit acetylcholinesterase, so
Ach accumulates in the synaptic cleft and acts as a
constant stimulus to the muscle fiber. The insects die
because their respiratory muscles contract and
cannot relax.
• Other poisons, such as CURARE, the poison used by
South American Indians in poison arrows, bind to the
Ach receptors on the muscle cell membrane and
prevent Ach from working. That prevents muscle
contraction, resulting in flaccid paralysis.
IRREVERSIBLE ACHE INHIBITOR
• Sarin gas
• Spastic paralysis
• Ventilator until AchE turnover
• This is a permanent Ach inhibitor.
The people who survive Sarin gas
attack are hospitalized. They have
to work to breathe (diaphragm
stops working, so they use their
abdominal muscles), so they need
a ventilator and pressure chambers
until there is a turnover in Ach after
enough gene expression (takes a
few weeks).
81
INHIBITORY NEURON BLOCKERS
• Tetanus toxin
• Blocks release of
inhibitory
neurotransmitters
• Muscles can’t relax
• Spastic paralysis
• Opposing flexor
and extensor
muscles contract
82
INHIBITORY NEURON BLOCKERS
• When you walk, it takes coordination with activating and inhibiting muscles.
Extension of leg activates quadriceps and inhibits hamstrings. Where does this
coordination originate?
• The somatic motor neurons innervate these muscles. When it reaches
threshold, will release ACh onto inhibitory neurons and excitatory neurons. This
causes flexor muscles to contract and extensor muscles to relax, then viceversa, so you can walk.
• If you have a toxin that prohibits release of inhibitory NT, then excitatory will
override, and cause more muscle contraction.
• That is what happens with tetanus toxin. When all of the NT is excitatory and
none are inhibitory, all muscle groups contract, causing back arching, and
diaphragm contracts too, and stays that way. Person dies from suffocation.
• Treatment is Ach-ase blockers like Curare. But you have to be careful with
that medicine…. Not just nicotinic, but muscarinic receptors also bind to ACh
in skeletal muscle. Atropine will also help.
SPIDER VENOM
• Black widow: causes
ACh release
• Lack of inhibitory
neurotransmitters
• Spastic paralysis
• Brazilian Wandering
Spider (banana spider)
• Spider venom increases
nitrous oxide release
• Most venomous of all
spiders/ more human
deaths
84
SPIDER VENOM
• Spider venom works like tetanus toxin.
• The Banana spider makes a lot of nitric oxide, which
stimulates receptors of in penis, causing it to flood
with blood, causing erection.
• Pharmaceutical companies decided to modify this
toxin and add it to Viagra, making the Viagra
longer lasting. Spider venom and Viagra both work
by blocking the enzyme that degrades nitric oxide.