Download Physio Lecture 11 Neurotransmitters

Physio Lecture 11 Neurotransmitters
General Sequence of Events at Chemical Synapses
• NTS synthesis and storage in presynaptic cell
• NTS release by exocytosis (Ca++ triggered event)
• Diffusion across cleft
• NTS reversibly binds to receptors (LGC) and opens gates, allowing ion diffusion
• NTS removal from synapse (destruction, diffusion away)
• NTS reuptake by presynaptic cell for recycling
NTS Action
• NT diffuses across synaptic cleft to bind to receptor (LGC) on postsynaptic membrane
• Can generate an electric signal there (excitatory EPSP’s or inhibitory 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 (inside of cell will be more positive, closer to AP; excitatory)
– K+ selective (inside of cell will be more positive, closer to AP; excitatory)
– Cl- selective (inside of cell will be more negative, farther from AP; inhibitory)
Neurotransmitters (NTs)
• The substance must be present within the presynaptic neuron
• Must be released in response to presynaptic depolarization, which must occur in a calcium
dependent manner
• 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 neuron or degradation by specific enzymes or a
combination of these
Know the following neurotransmitters (NTs):
Ach (excitatory), made in cholinergic neurons in the PNS, CNS, and ANS
Glutamate (powerful excitatory), made by all excitatory neurons (sensory pathways of CNS)
GABA (inhibitory); made in the CNS
Glycine (inhibitory); made in somatic motor neurons (spinal cord and brainstem motor neurons)
Catecholamines (released by adrenal glands in response to stress; they are part of the
sympathetic nervous system. They circulate in the bloodstream
Norepinephrine (mainly excitatory, can be inhibitory; secreted by neurons from CNS
and by neurons in sympathetic ganglia)
Epinephrine (excitatory; secreted by adrenal glands)
Dopamine ( inhibitory; secreted by neurons in substantia nigra portion of the midbrain)
Serotonin (consider it excitatory, although it can be inhibitory; secreted by neurons in CNS)
Know where in the nervous system the NT is made, and its functions (make a table). It may excite in one
type of cell but inhibit another cell.
Acetylcholine is found in the PNS and CNS and is one of many neurotransmitters in the ANS and the only
excitatory neurotransmitter used in the motor division of the somatic nervous system. Acetylcholine is
also the principal neurotransmitter in all autonomic ganglia.
ACETYLCHOLINE
• Neurons that make Ach are called cholinergic neurons
• Ach is used in neuromuscular junctions (NMJs). Therefore, cells that innervate skeletal muscles
are cholinergic neurons.
• Receptors that bind Ach are called cholinergic receptors
• Ach is the main NT of the sympathetic and parasympathetic ganglia in PNS
• Acetylcholine esterase (AChE) is the enzyme that degrades Ach into acetate and choline;
the choline is recycled to make more Ach, and the acetate is excreted
• When you want to remove Ach from the cleft, the AchE enzyme degrades it
• To make use of Ach, you have to make enough of it to overwhelm the AchE enzyme so the Ach
can get through to the ligands.
• Ach is made by the ChAT enzyme (choline acetyl transferase)which joins Acetyl-CoA to choline
in cholinergic neurons
GLUTAMATE
Glutamate is a powerful excitatory NT, widely used.
It opens Na and Na/Ca and Ca ligand gated channels.
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 dishomeostasis. 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 stimulation, inhibitory NTs will gain momentum. Too little glutamate leads to
psychosis, perceives reality differently than normal.
Glutamate
• Very important in CNS
• Nearly all excitatory neurons use it
• Antagonists to Glutamate receptor help stop neuronal death after stroke
• Too much- excitotoxicity due to unregulated calcium influx
• Too little, leads to psychosis (delusional, paranoid, lack of contact with reality
GABA and GLYCINE
These are the major inhibitory NTs.
Glycine is mainly used in somatic motor neurons, GABA in CNS.
GABA is more widespread. 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
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Major inhibitory neurotransmitter in CNS
Decreased GABA-seizures
Anticonvulsants target GABA receptors or act as GABA agonists
Benzodiazepines and ethanol trigger GABA receptors……use benzodiazepines during ethanol
detox.
Valium ( derivative of benzodiazepine)- increases transmission of GABA at synapses
Benzodiazepines enhance the effect of the neurotransmitter 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.
Glycine
• Glycine- also inhibitory
• Mostly in spinal cord and brainstem motor neurons
Catecholamines
Catecholamines are sympathomimetic "fight-or-flight" hormones that are released by the adrenal glands
in response to stress. They are part of the sympathetic nervous system. They are called catecholamines
because they contain a catechol group, and are derived from the amino acid tyrosine. The most
abundant catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine,
all of which are produced from phenylalanine and tyrosine. Many catecholamines serve as stimulants,
for example, MDMA (Ecstasy). Catecholamines are water-soluble so they circulate in the bloodstream.
Tyrosine is created from the amino acid phenylalanine, or it can be ingested directly from dietary
protein). It is then sent to catecholamine-secreting neurons. Here, many kinds of reactions convert it
Phenylalanine  TYROSINE  L-DOPA  dopamine  norepinephrine  epinephrine
Neurons that make dopamine are called Dopaminergic neurons
Neurons that make epinephrine or norepinephrine are called Adernergic neurons
Catecholamines
• Derived from amino acid tyrosine - common precursor
• Removed by reuptake into terminals or surrounding glial cells via sodium
dependent transporter
• Mono-amine oxidase (MAO) and catechol o-methyltransferase (COMT) degrade
catecholamines.
• MAO destroys epi and norepi and dopamine
• MAO inhibitors are used for depression, anti-anxiety, and Parkinson’s Disease
• A person on MAO inhibitors cannot take SYMPATHOMIMETIC medicines, such as
pseudofed, or anything else that acts like epi or norepi. It will cause more release
of epi and norepi, and the sympathetic (fight or flight) effects last too long
DISORDER OF PHENYLALANINE METABOLISM
Phenylketonuria (PKU)
Phenylketonuria (PKU) is the disease of a person who lacks the hepatic enzyme phenylalanine
hydroxylase. Siblings or first cousins who marry are more likely to have children with this disorder. This
is the enzyme that makes phenylalanine into tyrosine, which is then made into catecholamines. 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. This disorder is tested for in newborns by sticking the heel for a blood test.
Those who lack the enzyme need to stay on a modified diet (low in phenylalanine) or they will become
mentally deficient. Artificial sweeteners such as Sweet N Low, and diet sodas are high in phenylalanine,
and must be avoided. Once all the synapses are formed (after age 20), 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.
Phenylketonuria (PKU)
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A genetic, autosomal recessive disorder (1:20,000 births)
Lack of enzyme phenylalanine hydroxylase
Inability to convert phenylalanine (an amino acid) from the diet to tyrosine (another amino acid)
Accumulation of breakdown products of excess phenylalanine leads to neuronal
degeneration, seizures, poor motor development and irreversible mental retardation in a
developing child.
Testing at birth in many states, also CA. Heel stick blood sample
Prevented by dietary restriction on phenylalanine (No whole protein; source of all AA’s, no diet
sodas or artificial sweeteners). Must stay on diet in childhood and during pregnancy.
DOPAMINE
• Parkinson’s Disease (Parkinsonism)
• Loss of dopamine from neurons in substantia nigra of midbrain
• Resting tremor (“pill rolling”), bradykinesia (slow, shuffling gait = Parkinson’s shuffle)
• Treat with L-dopa (Crosses BBB, unlike dopamine) or MAO inhibitors
• Side effects (hallucinations, motor coordination problems)
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 will 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 Ldopa 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
• Also known as 5-hydroxytryptamine (S-HT)
• Selective serotonin reuptake (SSR) inhibitors are anti-depressant drugs
• Ecstasy causes more release of seratonin
• Mood elevator, “feel-good” neurotransmitter
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. 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!
TYPES OF LIGAND GATED RECEPTORS THAT RESPOND TO NTS
1) Ionotropic receptors bind to a NT and have a channel that extends into cell. They are the
receptor and the transporter
2) 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 a second messenger (either DAG or IP3) which goes
somewhere else in the membrane to open up another channel.
Ionotropic receptor
Metabotropic receptor
The second messenger of a metabotropic receptor can perform one or more functions:
1) Open specific ion channels
2) Activation of cAMP (affects long-term excitability of the neuron)
3) Activation of an enzyme inside the cell which may cause various changes
4) Activation of gene transcription (to form new proteins, chaning the metabolism; used especially
in making new memories )
Some NTs use different types of receptors. For example, Ach uses nicotinic (ionotropic) and muscarinic
(metabotropic) receptors.
You need to know the functional class (ionotropic vs. metabotropic) and the chemical classification
(cholinergic, dopaminergic, adrenergic) of the receptors we will cover. Know how they work and how
they bind.
Ionotropic Receptors
Nicotinic AChR (chemical classification is cholinergic)
Serotonin Glutamate
GABA
Glycine
Metabotropic Receptors
A sympathetic neuron can cause excitation in one organ and inhibition in another organ.
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.
Parasympathetic neurons that secrete Ach (cholinergic neurons) use muscarinic receptors (metabotropic)
Parasympathetic neurons that secrete epinephrine use adrenergic receptors (also metabotropic).
Sympathetic neurons that secrete Ach use muscarinic receptors.
Sympathetic neurons that secrete epinephrine primarily use adrenergic receptors (metabotropic), with
one exception: sweat gland with arrector pili muscles.
Therefore, both sympathetic and parasympathetic use metabotropic receptors.
Depending on where they are expressed, they function differently.
Parasympathetic neurons try to slow the heart rate. They will stimulate muscurinic receptors (Ach), and
will bind G protein and use DAG IP3 as a second messenger (metabotropic).
Sympathetic neurons try to speed up the heart rate. They will stimulate adrenergic (alpha and beta) receptors
(norepinephrine), and will also bind G protein and use DAG IP3 as a second messenger (metabotropic).
Muscarinic Acetylcholine receptors
Amanita muscaria
Parasympathetic effectors stimulated
Increased saliva, tears, diarrhea
Antidote is atropine.
Alpha and Beta-Adrenergic receptors
Alpha1-receptors: Bind G protein; activate diacylglycerol (DAG) and inositol
Triphosphate (IP3) as second messengers
alpha2 -receptors: Bind the inhibitory G-protein, restrain the adenyl cylase system,
reduce cAMP levels
Beta-receptors: Bind adenylate cyclase-stimulating G-protein, use cAMP as second
messenger.
Some glutamate receptors, many, many others
Huntington’s disease: rapid, jerky motions. The basal nuclei region of the brain helps regulate body
movements, and communicates with the motor cortex. It regulate stopping, starting, and coordination
of movements. Sends inhibitory impulses to motor cortex, so excitatory neurons are unbalanced,
unchecked, and the person has jerky sudden movements. Huntington’s disease is hereditary and does
not manifest until after they have children and pass on the bad gene.
Parkinson’s is a problem in the substantia nigra, which secretes dopamine, which helps to inhibit the
basal nuclei, sends inhibitory signals to motor cortex. People with Parkinson’s disease lack dopamine, so
they lose the ability to inhibit the inhibitory center of the brain. The motor cortex is shut down, and the
symptoms are the opposite of Huntington’s disease; they cannot initiate movements.
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,
the sympathetic system will gain more control. If you stimulate the parasympathetic system, it will gain
control. Para and sym are both on at the same time. The question is when does the symp have more
control? When does the parasympathetic systme have more control?
Does a particular drug mimic the parasympathetic system? If yes, then if parasympathetic has more
control, what will the body be doing? The heart rate is lower. 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).
Ionotropic classification means the receptor and channel is the same protein. Ions move by passive
diffusion. Metabotropic classification means that the NT triggers a series of enzymatic reactions in the
cell, effecting part of metabolism. There are two types of metabotropic receptors:
1) muscarinic acetylcholine (mostly used by parasymp)
2) adrenergic receptors (mostly used by symp)
The heart has receptors that allow both para and sym to have effects. A lot of involuntary effectors
(such as the heart) are dually innervated. We need both types of receptors on those organs so they can
adjust their physiology.
Major Intracellular Transduction Pathways Used by metabotropic receptors
Metabotropic vs. Ionotropic pathways: how are they similar and different? (Compare and contrast)
Step one: need NT to bind to receptor.
Ach binds to muscurainic
Norepi and epi bind to adrenergic
Step 2: The G proteins activates the alpha subunit
The G-protein (both use it) is a peripheral protein, found inside every cell of the body. There are
different types. All G-proteins are trimers (3 subunits), consisting of alpha, beta, and gamma subunits.
When the NT binds to the receptor, the G-protein will bind to a high energy molecule, call GTP, then
the alpha subunit breaks away from the other two subunits. There are diff types of G proteins. They are
GS (stimulating G protein) or GI (inhibiting G protein), depending on the alpha subunit. 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: Activation of the effector protein
The effector proteins used by para is called phospholipase 2 (PL2).
The effector proteins used by symp is adenelocyclase.
The effector protein is what makes the second messenger.
Step 4: Synthesis of the second messenger
There are 3 types of second messengers: IPG, DAG, and calcium.
In the sympathetic system, cyclic ATP is the second messenger.
Step 5: The late effector protein
Sym is protein kinase A
Para is protein kinase B
We ultimately want kinase activity, which phosphoralyates other proteins in a cell. It does not mean it
is revved up; it might be muted. The activity level of the cell is changed.
When sym is engaged more, the systems react en mass, overall systemic change.
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 HR. The heart cells
like to beat fast. The parasym causes the second messenger pathway that leads to slowing the heart
rate. The post op patient cannot allow themselves to become overly anxious, angry, or sexually aroused
after heart transplant. The sym system can release epi (which is a hormone secreted by adrenal glands
as well as a NT made by neurons). It will take a heart replacement patient a long time to come down off
an increase in HR (due to anger, anxiety, etc) because they have to wait for a hormone change. There
are no hormones to calm you down. There is global stimulus of adrenergic receptors.
Signaling by GPCRs
There is a G protein (GP) that binds to the NT. The GP binds to GPT, then the alpha unit activates adenyl
cyclase, which increases cAMP. Adenylate cyclase uses a hydrolase enzyme to attach phosphate onto
ATP, making it into a cyclical structure which is now called cAMP, which is a derivative of ATP.
Adenylate cyclase and guanylate cyclase make cyclic AMP and cyclic GMP
Protein kinase A
Protein kinase A consists of two big blue regulatory subunits and two pink catalysts. It is a quaternary
structure (4 subunits). If there were no regulatory subunits, the catalytic subunits will have a great time.
When cyclic AMP levels are high, it binds to the regulatory subunit, causes catalytic subunits to
disengage and have a good time, attaching phosphate groups to lots of other proteins, which changes
their activity. cAMP causes dissociation of protein kinase A, and proteins will become phosphorylated,
changing the cell’s activities.
Phosphorlyated proteins are not always increased in activity. Sometimes they become slower. But the
activity is changed.
For the below picture:
The blue squiggly thing is a protein receptor for norepinephrine.
Norepi appears inside the receptor.
The G protein binds to GTP, the alpha subunit disengages.
Adenylcyclase is activated, then there is synthesis of cAMP (the 2nd messenger)
Protein kinase A can be regulatory (yellow) or catalytic (blue).
cAMP binds to regulatory proteins, then the potassium leak channel becomes blocked.
The sym primarily uses the cAMP pathway.
The heart rate increases.
Exercise stimulates the sym nervous system, but the cardiac cycle is shortened to allow this. To shorten
the cardiac cycle, the cardiac mm has to depolarize and reach threshold AP faster. How do you reach
threshold faster? How do you get inside of cell more positive faster? Increase Na input, or block
phosphoralase, which blocks K from leaving cell. That is the #1 way that sym system uses to increase
the heart rate.
When an adregnergic receptor is stimulated, G protein will stimulate adenocycline
Above is parasympathetic nervous system.
There are three second messengers in the parasympathetic system: DAG, IP3, and calcium
Top left corner: metabotropic receptor. G protein has alpha subunit come off, activates first protein, PLC
(Phospholipase C). Phospolipids (PL) are in the membranes. PLC cuts a special PL within the cell
membrane, called PIP2. PLC cuts things into two fragments. One smaller fragment stays in cell
membrane, and it is called DAG, which activates protein kinase (which phosphorylates a protein). DAG
binds to a muscarinic receptor. The IP3 binds to endoplasmic reticulum (ER), where a lot of calcium is
stored, causing calcium to pour out.
Calcium activates a calcium kinase.
The metabotropic receptors used by he ANS have different NTs, diff metabotropic receptors, and
different 2nd messengers.
How can we use the parasympathetic system to make the heart cells less active?
Do something that increases phosphorylation, which opens potassium channels, making the inside of
the cell more negative (hyperpolarized). The number one way HR is regulated is by potassium.
NT postsynaptic response and gene expression
• Open channels
• Alter gene expression
• Second messenger activation can lead to phosphorylation of proteins that in turn regulate
gene transcription
The pathways can also alter gene expression, which can generate new protein channels in the cell
membrane, or can lead to the shut-down of these proteins and channels.
2nd messengers can also be used by hormones, not just NT’s.
They change the cells physiology
Drugs and Toxins: Spastic paralysis vs. flaccid paralysis
A muscle cannot be maintained in a contracted state. If it stayed contracted, you would be paralyzed.
Sodium VGC Blockers
• Lidocaine- used as anesthesia
• Tetrodotoxin-puffer fish and newts (TTX)
• Saxitoxin- caused by red tide; dinoflagellate; accumulates in shellfish (SXT)
• Flaccid paralysis
Na VGC blockers will block the opening of the sodium, 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:
• It is a protease that breaks down one of the fusion proteins (docking proteins that anchor the
vesicle to the membrane)
• Inhibits neurotransmitter release
• Undercooked turkey; dented cans
• Flaccid paralysis
• “BOTOX”
One type of clostridium causes botulin toxin.
Synaptic vesicles need to fuse with the synaptic membrane, and they need a protein to do this. Botulin
toxin destroys the proteins that are the docking proteins. It is a protease. Facial muscles are skeletal
muscles. Botox injections block the ability of the nerve to release the NT, mm remains in flaccid
paralysis.
mACH-R blocker/ competitor
• Atropine
• Flaccid paralysis
• Smooth muscle, heart, and glands
Muscarinic Ach receptor (mACH-R) blockers block the parasympathetic system, so the sympathetic gets
more control.
If you block receptors on intestines for peristalsis, you will get flaccid paralysis.
If heart has stopped, inject atropine to block mACH receptors on cardiac muscles, and heart rate will
increase.
Your iris has 2 types of smooth muscle. It has circular bands of smooth muscle, and radial fibers like
spokes on a wheel. The radial fibers have alpha receptors (adrenergic). The sphincters have Ach
muscarinic receptors. If mACH-R binds Ach, the pupils will close. If we block Ach, the radials 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
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 Blockers
• Neostigmine
• Physostigmine
• Spastic paralysis
• These drugs are used to treat Myasthenia Gravis (autoimmune disorder). The body’s antibodies
attacks the nicotinic Ach receptors, so there are fewer of them, less Na coming in, less APs. Eyes
become fatigued. Force open the eyelids, have them look up, will cause fatigue, and their lids
will droop (ptosis). Give a medicine to inhibit Ach.
Neostigmine and Physostigmine are temporary Ach inhibitors which block the enzyme that degrades
Ach into acetate and choline. If you take Neostigmine or Physostigmine, you would potentiate the
effects of Ach (will last longer), will stimulate the muscles, causing spastic paralysis.
AChE irreversible inhibitor
• DFP- di-isopropyl fluorophosphates
• Sarin gas
• Spastic paralysis
• Ventilator until AchE turnover
These are permanent Ach inhibitors. 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).
Inhibitory Neuron Blockers
• Tetanus exotoxin
• Blocks release of inhibitory neurotransmitters
• Muscles can’t relax
• Spastic paralysis
• Opposing flexor and extensor muscles contract
When you walk, it takes coordination with activating and inhibiting muscles. Extension of leg activates
quad and inhibits hamstrings. Where does this coordination originate? The somatic motor neurons
innervate these muscles. When it reaches threshold, will release Ach and reach threshold. When you
inhibit it, it happens in the cell body, which is in the spinal cord. When you take a step forward, the
motor neuron synapses on a lower motor neuron, where it releases inhibiting NT (like GABA or Glycine),
so the lower motor neuron will be inhibited. 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. Somatic motor neurons release NT, all muscle groups contract, get back arching, and diaphragm
contracts too, and stays that way. Treatment is Ach blockers like Curare. Have to be careful. Not just
nicotinic, but muscarinic 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) and Viagra?
– Spider venom increases NO release
– Viagra blocks enzyme that degrades NO
– Most venomous of all spiders/ more human deaths
Spider venom works like tetanus toxin. Banana spider lives between bananas.
Symptoms include an erection in males. The Banana spider makes a lot of nitric oxide, which stimulates
receptors of corpora cavernosa in penis, causing it to flood with blood. Pharmaceutical companies
decided to modified this toxin and add it to Viagra, making the Viagra longer lasting. It works by
blocking the enzyme that degrades NO.