Physiology of a Neuron from Dendrite to synaptic transmission
Function of Dendrites in Stimulating Neurons
• Dendrites spaced in all directions from 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
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-).
What would happen to the resting membrane potential if these channels opened?
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.
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.
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; stimuli from two different presynaptic neurons
(different locations)
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.
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.
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
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
 energy conservation
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. Patients have a difficult time describing their
symptoms. 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 the diagnostic dilemma begins.
The Synapse
• Structures important to the function of the synapse:
– presynaptic vesicles
• contain neurotransmitter substances to excite or inhibit postsynaptic neuron
– 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.
– depolarization of the presynaptic membrane by an action potential opens Ca2+ channels
– influx of Ca2+ induces the release of the neurotransmitter substance
• Postsynaptic membrane contains receptor proteins for the transmitter released from the
presynaptic terminal.
• 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.
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
Synaptic Events
• 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
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
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?
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
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….
• 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.
• 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
• Cholinergic (Ach)
• Catecholamines
• Adrenergic
• 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)
• Muscarinic (mACh)
• Nicotinic (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
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)
• Very important in CNS
• Nearly all excitatory neurons use it
• Antagonists to Glutamate receptor help stop neuronal death after stroke
• Too much glutamate causes excitotoxicity due to unregulated calcium influx
• Too little, leads to psychosis (delusional, paranoid, lack of contact with reality)
• 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.
and Glycine
GABA is the major inhibitory neurotransmitter in CNS
Decreased GABA causes seizures
Anticonvulsants target GABA receptors or act as GABA agonists
Valium increases transmission of GABA at synapses
Benzodiazepines and ethanol (drinking alcohol) both trigger GABA receptors……use
benzodiazepines during alcohol detox.
 Glycine- also inhibitory
 Mostly in spinal cord and brainstem motor neurons
• 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
• GABA agonists (drugs that act like GABA, such as anti-convulsants) can also be given.
• 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.
• 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.
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
• Serotonin
• Secreted by neurons in the CNS
• Its action is mainly excitatory. It can excite one cell but inhibit another.
• Epi and norepi are made from 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)
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.
• 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.
• 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.
• Using too much of the drug “Meth” will kill Dopaminergic neurons, causing Parkinson’s
• 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
• Synthesized from tryptophan
• Serotonin reuptake inhibitors are anti-depressant drugs
• Ecstasy causes more release!
• Mood elevator, “feel-good” neurotransmitter
• 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!
Phenylalanine  TYROSINE  L-DOPA  dopamine  norepinephrine  epinephrine  serotonin
• 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.
• 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
Ways to classify NT receptors
• Functional Classification
• Ionotropic
• Metabotropic
• Structural Classification
• ACh Receptors
• Muscarinic ACh receptors
• Nicotinic ACh receptors
• Adrenergic Receptors
• Alpha 1 and Alpha 2 receptors
• Beta 1 and Beta 2 receptors
• Dopaminergic Receptors
• Serotonergic Receptors
• Glutamate, GABA, and Glycine Receptors
• 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.
• G protein receptors are involved in many diseases, and are also the target of approximately 30%
of all modern medicinal drugs.
• 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
• 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.
Structural classification of NT Receptors
• 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 Dopamine, Serotonin, Glutamate, GABA, and Glycine, but we will not cover
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. These receptors are also found in the CNS.
Muscarinic acetylcholine receptors
• All mACH receptors use the G-proteins, so their functional classification is “metabotropic”.
• Drugs that block the mACh receptor include:
• Medicines that treat Parkinson's disease
• Atropine (to dilate the pupil for eye exam)
• Scopolamine (to prevent motion sickness)
• Ipratropium (treatment of COPD)
• The G-protein can be excitatory or inhibitory, depending on which ion channel it opens.
Nicotinic acetylcholine receptors
• All nACH receptors use a ligand-gated ion channel mechanism.
• The opening of an ion channel, permits either K+, Na+, Cl- or Ca++ to diffuse into or out of the
• If a K+ channel opens, K+ will leak out of the cell. If the Cl- channel opens, Cl-, it will leak into the
cell. Both of these outcomes will inhibit an action potential (inhibitory). GABA and Glycine are
the two NT’s that will do this.
• If a Na+ or Ca++channel opens, those will leak into the cell, causing an action potential
(excitatory). Glutamate, serotonin, and ACH using a nACH receptor will do this.
• The functional classification of all nACH receptors is “ionotropic”.
Ionotropic Receptors
u Nicotinic ACH
u Serotonin
u Glutamate
u Glycine
What neurons secrete ach?
• All preganglionic neurons (sympathetic and parasympathetic) and postganglionic
parasympathetic neurons secrete Ach, using nicotinic receptors there.
• About 98% of postganglionic sympathetic neurons secrete norepi and use an adrenergic
receptor, but 2% of postganglionic sympathetic neurons secrete Ach (those that supply the
sweat glands), and use muscarinic receptors.
Effects 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
• 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.
Nicotinic Receptors
• Nicotinic acetylcholine receptors can be blocked by curare, hexamethonium and toxins present
in the venoms of snakes and shellfishes, like α-bungarotoxin. Drugs such as the neuromuscular
blocking agents bind reversibly to the nicotinic receptors in the neuromuscular junction and are
used routinely in anesthesia.
Nicotinic receptors are the primary mediator of the effects of nicotine. In myasthenia gravis, the
receptor at NMJ is targeted by antibodies, leading to muscle weakness. Muscarinic acetylcholine
receptors can be blocked by the drugs atropine and scopolamine.
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 th above receptors use G-Protein (the functional classification is metabotropic)
Metabotropic Receptors
u Muscarinic Acetylcholine receptors
 Mostly used by post-ganglionic parasympathetic neurons
u Alpha and Beta-Adrenergic receptors
 Mostly used by sympathetic neurons
u Dopaminergic receptors
 Mostly used by sympathetic neurons
Drugs and Toxins
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.
Vesicle blockers
• Clostridium botulinum:
• Bacterium that has a protease (enzyme that breaks down proteins). Botulism toxin 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.
Sodium VGC Blockers
• Lidocaine- used as topical anesthesia
• Tetrodotoxin-puffer fish and newts (TTX)
• Saxitoxin- caused by red tide; a type of red algae called dinoflagellates accumulates in shellfish
• Curare: poison arrows
All of the above four things cause flaccid paralysis
Na VGC blockers will block the sodium channel so you can’t have an action potential. 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!
Curare is a nACH-R blocker/ competitor. It is from tree sap. Large dose: asphyxiation
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. This is considered a
Na+ VGC blocker.
mACH-R blocker/ competitor
• Atropine
• Flaccid paralysis
• Smooth muscle, heart, and glands
• Atropine and other mACH blockers are not classified as a Na+ VGC blocker because they use
mACH receptors, which are metabotropic (use the G protein), so atropine blocks the Na+ VGC
indirectly. Only substances that use ionotropic receptors (such as nACH) can block the Na+ VGC
directly. Examples are lidocaine, tetrodotoxin, saxitoxin, and curare. Atropine is not in this
category, even though all of them result in flaccid paralysis.
• mACH receptor blockers will block the parasympathetic system, so the sympathetic gets more
• 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.
• 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.
Atropine is a competitive muscarinic acetylcholine receptor antagonist. It is a naturally occurring
alkaloid extracted from the deadly nightshade plant (Atropa belladonna). The species name
"belladonna" ("beautiful woman" in Italian) comes from the original use of deadly nightshade to dilate
the pupils of the eyes for cosmetic effect. Both atropine and the genus name for deadly nightshade
derive from Atropos, one of the three Fates who, according to Greek mythology, chose how a person
was to die.
In general, atropine counters the "rest and digest" activity of glands regulated by the
parasympathetic nervous system. This occurs because atropine is a competitive antagonist of the
muscarinic acetylcholine receptors. Atropine dilates the pupils, increases heart rate, and reduces
salivation and other secretions.
Secretions and bronchodilatation
Atropine's actions on the parasympathetic nervous system inhibit salivary and mucus glands. The
drug may also inhibit sweating via the sympathetic nervous system. This can be useful in treating
hyperhidrosis, and can prevent the death rattle of dying patients. Even though atropine has not been
officially indicated for either of these purposes by the FDA, it has been used by physicians for these
purposes. Atropine is not an actual antidote for organophosphate poisoning such as insecticides or
nerve gas. However, by blocking the action of acetylcholine at muscarinic receptors, it serves as a
treatment for poisoning by these toxins, such as sarin gas. Troops who are likely to be attacked with
chemical weapons often carry autoinjectors with atropine for rapid injection into the thigh muscles.
Atropine is given as a treatment for SLUDGE syndrome (salivation, lacrimation, urination,
diaphoresis, gastrointestinalmotility, emesis) symptoms caused by organophosphate poisoning.
Another mnemonic is DUMBBELSS, which stands for diarrhea, urination, miosis, bradycardia,
bronchoconstriction, excitation (as of muscle in the form of fasciculations and CNS), lacrimation,
salivation, and sweating (only sympathetic innervation using Musc receptors).
A common mnemonic used to describe the physiologic manifestations of atropine overdose is: "hot
as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter". These associations
reflect the specific changes of warm, dry skin from decreased sweating, blurry vision, decreased
sweating/lacrimation, vasodilation, and central nervous system effects on muscarinic receptors, type
4 and 5. This set of symptoms is known as anticholinergic toxidrome, and may also be caused by
other drugs with anticholinergic effects, such as scopolamine, diphenhydramine, phenothiazine
antipsychotics, and benztropine.
AchE (acetylcholine esterase) Blockers
• Neostigmine
• Physostigmine
• Spastic paralysis
• These drugs are used to treat Myasthenia Gravis, an autoimmune disease that causes ptosis
(droopy eyelid)
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).
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
It is used to improve muscle tone in people with myasthenia gravis and routinely in anesthesia to
reverse the effects of muscle relaxants at the end of an operation.
It can also be used for urinary retention resulting from general anesthesia and to treat curariform
drug toxicity.
Another indication for use is the Ogilvie syndrome which is a pseudoobstruction of the colon in
critically ill patients.
Sometimes, hospitals use an intravenous version of neostigmine to delay the effects of snakebite
Though it is one of only two treatments available for myasthenia gravis, this drug is no longer
available in the United States to anyone using the Medicare Part D program. The other drug is
Pyridostigmine, which has to be used with caution in people with asthma.
Neostigmine will cause slowing of the heart rate (bradycardia); for this reason it is usually given
along with a parasympatholytic drug such as atropine.
Less serious side effects:
headache, drowsiness;
mild nausea, vomiting, gas;
urinating more than usual;
cold sweat, warmth or tingly feeling; or
mild rash or itching.
Serious side effects:
extreme muscle weakness;
slurred speech, vision problems;
feeling like you might pass out;
severe stomach cramps or diarrhea;
trouble breathing, cough with mucus;
fast or slow heart rate;
seizure (convulsions);
worsening or no improvement in your symptoms of myasthenia gravis.
 The most commonly used anticholinesterase is "Mestinon". This comes in 60 milligram
(mg) or 10 mg tablets and is released immediately. “Mestinon TimeSpan" is a 180 mg
tablet in which 60 milligrams is released immediately and the remaining 120 milligrams
are released over several hours. TimeSpan is usually prescribed for patients who require
medication throughout the night (this allows for comfortable, uninterrupted sleep and
reasonable strength in the morning). Timespan's uneven release provides less predictable
results than with ordinary Mestinon and is usually not recommended for day time use, but
some myasthenics prefer taking it. Liquid "Mestinon" syrup is for children and for adults
who have trouble swallowing pills.
Diagnosis of MG
 Tensilon Test
1. Baseline assessment of the cranial muscle strength should be done first
2. Edrophonium chloride (Tensilon) is administered, which is a medication that inhibits the
breakdown of Ach, making it available for use. If muscle strength improves = positive
for MG. (muscle strength will only last for approx. 5mins). FYI: Atropine should be
available as antidote for Tensilon
Medications for MG
Anticholinesterase Agents, which inhibit breakdown of Ach and prolong its effect
 Pyridostigmine (Mestinon) is the Drug of Choice
 use cautiously on patients with bronchial asthma, bradycardia, arrhythmias,
epilepsy, recent coronary occlusion, renal impairment, hyperthyroidism or
peptic ulcer
 Adverse reaction: bradycardia, cardiac arrest, bonchospasms,
 Neostigmine (Prostigmin)
 Note: do not give medication on patients with bladder or bowel obstruction
Nursing Considerations for patients with MG
 Monitor respiratory status
 Check gag reflex before feeding
 Use energy conservation measures
 Provide small, high calorie meal give meals when meds are peaking
 Sit upright when eating and use thickener as necessary
 Lubricating eye drops and eye patch at night if clients were unable to completely close their
MYASTHENIC CRISIS (undermedication)
CHOLINERGIC CRISIS (overmedication)
Respiratory muscle weakness (mechanical
Muscle twitching to the point of respiratory muscle
weakness (mechanical ventilation)
Weakness, incontinence, fatigue
Hypersecretions (nausea, diarrhea) hypermotility
Tensilon test =temporary improvement if
Tensilon test= no effect or worsens the symptoms.
Symptoms improve after atropine (anticholinergic) is given
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).
Inhibitory Neuron Blockers
• Tetanus toxin
• 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 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 vice-versa, 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
• 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
What to focus on
• Know the classifications, including metabotropic vs ionotropic.
• Which NT is for skeletal muscle? Smooth? Cardiac? Glands?
• Which NT is used for the illnesses mentioned (stroke, myasthenia gravis)?
• How does alcohol affect a NT or its receptors?
• Know the effects of Alpha, Beta (1 and 2), muscarinic, and nicotinic receptors.
• Know the drugs and toxin section VERY WELL.
• Where are the nACH and mACH receptors found in the body? What part of the ANS do
they effect: Sympathetic or Parasympathetic?
• Know the diseases, and which receptors are affected.
• Know which diseases cause flaccid vs. spastic paralysis.
• Know which branch of the ANS (sym vs parasymp) uses metabotropic and which uses
ionotropic receptors.