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Laith Khreisat

Ahmad Ali Massad

Faisal Muhammad

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* Note: I tried my best to include everything mentioned in the slides, but

feel free to refer back to them in case I missed anything.

* Last time we talked about the types of neurons and receptors, we

mentioned that there are ionotropic receptors and metabotropic receptors,

the difference between them is that ionotropic receptors are fast and don’t

use second messenger systems, metabotropic receptors on the other hand

are slow and they use second messenger systems.

* Some important transmitters:

1- Acetylcholine (ACh) 2- Monoamines 3- Amino acids

4- Polypeptides 5- Monoxide Gases (CO and NO)

1-Acetylcholine (ACh) as NT:

# It is the most important and most common one.

It is synthesized by an enzyme called ‘Choline acetyltransferase’ (ChAT)

which catalyzes the ‘transfer’ of an acetyl group from acetyl-CoA to choline

yielding acetylcholine (ACh). *note that ChAT is synthesized in the cell body

and is transported to the nerve terminal, it synthesizes ACh in the

terminal*

The enzyme that inactivates ACh is Acetylcholinesterase (AChE):

Present on postsynaptic membrane or immediately outside the membrane.

Prevents continued stimulation.

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How is ACh broken down?

AChE breaks it down into acetic acid and choline

Choline can be reuptaken actively by secondary active transport (co

transport).

The life cycle of ACh:

After being synthesized by ChAT, ACh is

stored inside vesicles and later released

in response to an action potential. After

release, ACh binds to its receptor

(nicotinic or muscarinic). Once it is

dissociated from its receptor, AChE

breaks it down into choline and acetic

acid, choline is going to be recycled.

*note that neuropeptides are not

recycled back once released, unlike

neurotransmitters*

Choline is reuptaken through choline transporters using co-transport

mechanism with Na+ (Co means together), so it can be used again to form

ACh.

Remember: Co-transport is also called ‘symport’ and counter-transport is

also called ‘antiport’ (such as Na+/ Ca++ exchanger in cardiac muscles)

** Neuropeptides are synthesized in the cell body (soma) and they are

transported to terminals by axonal transport which is very slow, that’s why

they are secreted in small quantities.

# ACh distribution:

It is found in Peripheral N.S:

1- Excites somatic skeletal muscles (neuro-muscular junction between motor

neurons and skeletal muscles) the only neurotransmitter between a motor

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neuron and a skeletal muscle is ACh , and its receptor is nicotinic receptor

subtype N2 , but remember that the neuro-muscular junction is not

parasympathetic , it is motor somatic .

2- Autonomic NS:

Ganglia (of both sympathetic and parasympathetic and their receptor is

nicotinic receptor subtype N1)

Parasympathetic NS---Neuroeffector junction (in postganglionic neuron

between the postsynaptic neuron and the gland or smooth muscle supplied

by the parasympathetic nervous system)

Few sympathetic NS –Neuroeffector junction (like sweat glands).

3- Central nervous system – widespread – ACh acts as a neurotransmitter in

basal ganglia and some areas in the cerebral cortex and cerebellum.

# ACh receptors:

ACh can be both an excitatory and an inhibitory NT (depending on the type

of receptor involved).

–Causes the opening of chemical gated ion channels.

•Nicotinic ACh receptors:

–Found in autonomic ganglia (N1 subtype) and skeletal muscle fibers (N2

subtype).

•Muscarinic ACh receptors:

–Found on the plasma membrane of smooth and cardiac muscle cells, and in

cells of particular glands.

We have M1 and M2 receptors , it is not important to know where it is found

, but for example in smooth muscle of GI we have M2 and in Central nervous

system we have M1.

*Nicotinic Receptor:

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–Linked to Na +and K+ channels so it is ionotropic.

–Opens on ligand binding

–Depolarization of target (neuron, muscle)

–Stimulated by Nicotine ( Agonist).

–Blocked by Curare (Antagonist).

-Motor endplate (somatic) N2 subtype

- All autonomic ganglia and hormone producing cells of adrenal medulla

N1 subtype

** We know that motor neurons cause contraction in skeletal muscles,

curare as an antagonist causes relaxation in these muscles (prevents

contraction) that’s why it can be used as an anesthetic (مخدر (.

*Muscarinic Receptors:

Many muscarinic receptors have been identified (M1-M5).

•“Muscarinic” subtype Receptor: M1

–Use of signal transduction system (second messenger system)

•Phospholipase C, IP3, DAG, cytosolic Ca++

** These receptors act on G proteins that activate phospholipase C,

phospholipase C converts phospholipids into DAG (diacylglycerol) and IP3

(inositol-1, 4, 5-triphosphate). IP3 enters the endoplasmic reticulum

stimulates the release of Ca++ activates protein Kinase C.

Remember: protein kinase C is Ca++ and phospholipids dependent, it uses

Ca++ and phospholipids as second messengers (not Ca++ alone and not

phospholipids alone but both of them).

On the other hand, protein kinase A is c-AMP dependent protein kinase, it

uses C-AMP as a second messenger.

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-Found on all parasympathetic target organs

–Some sympathetic targets (endocrine sweat glands)

–Blocked by Atropine, etc.

–Effects on target:

Heart: Decreases the heart rate but don’t decrease contraction, because it

doesn’t supply the ventricles, it supplies the atria, AV & SA nodes.

GI tract: It acts on the gastrointestinal smooth muscles that cause

contraction of the GI tract.

-Colic مغص() : Occurs due to muscular contractions in the GI tract in an

attempt to relieve an obstruction by forcing content out. *there is also renal

colic which is caused by ureter stones (kidney stones)*

-ACh increases all the functions of the GI tract like secretion, reabsorption,

contraction, motility, it also increases the blood flow to the GI tract.

•’’Muscarinic” subtype: M2

–Use of signal transduction system

•Via G-proteins (Gi type) decreases c-AMP levels , or opening of K+ channels

in the heart ( this mechanism differs from M1 receptor mechanism )

–Effect on target: cell specific

–Blocked by Atropine (antagonist).

# Cholinergic Agonists:

•Direct: that means the substance binds ‘directly’ to the receptor and

activates it.

–Muscarine

–Nicotine

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•Indirect : If you inhibit AChE (acetylcholinesterase) ACh will remain acting

for a longer period of time , these indirect agonists do not bind to the

receptor directly , instead , they inhibit the breakdown of ACh ; thus ,

prolonging its action.

- AChE inhibitors :

_* Some drugs and toxic substances like organophosphates are indirect

agonists. organic phosphates are used as pesticides (kill insects) ,

bactericides (kill bacteria ) , bacteriostatics ( stop bacteria from reproducing

), they can also cause poisoning to humans.

These substances inhibit AChE causing the following effects:

1- Increased saliva and tear production

2- Pupil constriction (miosis)

3- Twitching (contraction in the muscles)

4- Bronchial constriction

The patient that has organophosphate poisoning is given atropine (to stop

these effects by blocking muscarinic receptors *antagonist*) ( we continue

to look at the patient’s pupil until it returns to its normal state)

** Nerve Gas ( sarin ) (which is an organophosphorus compound) causes

constriction of the bronchi ) thus it becomes difficult to breathe) and also

causes increase in secretion , twitching and so on . It spreads very fast

because gases are lipid soluble . To block these effects we give the patient

atropine.

Remember : sympathetic nerves cause dilation of the pupil and bronchioles

but parasympathetic nerves cause constriction of the pupil and bronchioles.

# Cholinergic Antagonists:

Nicotinic -Curare

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Muscarinic –Atropine

* Ligand-operated ACh channels:

ACh binds to the receptor , the

receptor itself is an ion channel, so

the channel is opened

Ionotropic receptor , as in

nicotinic receptors.

* G protein operated ACh channels:

ACh binds to the receptor Activates G protein α subunit dissociates

then it either opens a channel or

activates second messenger

systems (Metabotropic receptors)

, as in muscarinic receptors.

2- Monoamines as NT:

# They are derivative from tyrosine

and tryptophane.

Catecholamines - Indolamines -

Dopamine – DA Serotonin -5-HT

Norepinephrine -N

Epinephrine –E

# What is the difference between norepinephrine and epinephrine??

Both of them come from tyrosine but norepinephrine doesn’t have a methyl

Group ( CH3) and epinephrine has a methyl Group so by adding a ( CH3) to

norepinephrine it becomes epinephrine.

:Synthesis of Monoamine NT

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# β – Receptor mechanism of action

Norepinephrine ( NE) and Epinephrine ( Epi) bind to the receptor , the

receptor is a G protein coupled receptor , α subunit dissociates , activates

adenylyl cyclase , adenylyl cyclase coverts ATP to c-AMP , c-AMP activates

protein Kinase A ( we have mentioned that protein Kinase A is c-AMP

dependent protein Kinase ) , protein Kinase A then will phosphorylate

proteins ( or sometimes may open channels ) , phosphorylation of proteins

will activate or deactivate certain process in the cell , these responses differ

from one cell to another cell depending on the enzymes activated .

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* Note : G protein is inactive when bound to GDP, it is activated by replacing

GDP with GTP.

# Norepinephrine (NE) as NT:

•NT in both PNS and CNS.

•PNS ( Peripheral nervous system) :

–Smooth muscles, cardiac muscles and glands.

*It causes vasoconstriction (increases blood pressure)

The blood vessels are supplied only by the sympathetic nervous system, so

if you increase sympathetic tone vasoconstriction , and if you decrease

sympathetic tone vasodilatation.

( The parasympathetic nervous system has no effect on ‘blood vessels’

“although it can cause vasodilation by other means in the GI glands for

example” , but it does not innervate the blood vessels directly).

So we have vascular tone which is the basal level of constriction , vessels are

constricted a little , the basal level of constriction is called tone , so the

inhibition of norepinephrine will cause dilation of the vessels “vasodilation”.

( also, skeletal muscles have muscle tone that either increases or decreases ,

when it is increased , this causes tetanus or spastic “ over activity in muscles

“ ).

* Cardiac muscles : Increases heart rate , Increases contractility.

•CNS: it is found in Locus coeruleus which is very important for sleep (REM

sleep).

- Affects general behavior.

# Adrenergic Receptors:

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*These receptors respond to catecholamines ( epinephrine and

norepinephrine)

*Two types of receptors are known α and β .

*The alpha receptors are subdivided into α1 and α2 receptors, also α1 (that

increases Ca++ cocentration) subdivides into ( α1a , α1b , α1d ) and α2 ( that

inhibits adenylyl cyclase ) subdivides into ( α2a , α2b , α2c ).

* Beta receptors (that stimulate adenylyl cyclase) are subdivided into β1 (

found in the heart ) and β2 ( found in lungs ) and β3 ( found in adipose

tissue ).

* Every receptor works via different mechanism.

* It is very important to know the types of receptors in order to give proper

treatment , for example: α1 Vessels causes vasoconstriction , so if you

want to treat hypertension you give the patient a vasodilator ( we give him a

selective α1 blocker “ affects only α1 and not α2”)

* In treatment we give selective blockers that only affect one specific

receptor.

# α1 Receptor :

–Stimulated by NE, E,…

– Found in blood vessels of skin, mucosa, abdominal viscera, kidneys, salivary

glands

–Causes vasoconstriction, sphincter constriction, pupil dilation

# α2 Receptor :

–Stimulated by, NE (norepinephrine), E (epinephrine) ,..…

–Found on the membrane of adrenergic axon terminals (pre-synaptic

receptors), platelets

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** Platelets : when stimulated they aggregate ( clock together ) , this is

important for blood clotting .

**Antiplatelets ( الدم اتمميع ) prevent clotting , like “aspirin”

–Inhibits further release of NE (autoreceptor)

–Promotes blood clotting, and in the pancreas decreases insulin secretion

# β1 Receptor :

-Stimulated by E, ….

–Found mainly in heart muscle cells

–Increases heart rate and the strength of contraction # β2 Receptor :

–Stimulated by E ..

– Found in lungs, most other sympathetic organs, blood vessels serving the

heart (coronary vessels)

–Causes dilation of bronchioles & blood vessels (coronary vessels), and

pregnant uterus

- In the GI tract : causes relaxation of smooth muscles , decreases secretion ,

motility , decreases blood flow to the GI tract.

# β3 Receptor :

–stimulated by E.… ,

–Found in adipose tissue,

–Stimulation of lipolysis (breakdown of lipids)

3- Amino Acids as NT:

•Glutamate acid and aspartate acid: –Excitatory Amino Acid (EAA)

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•Gamma-amino-butyric acid (GABA) and glycine: –Inhibitory AA 4- polypeptides as NT:

•CCK: (cholecystokinin ) controls appetite –Promotes satiety following meals. (satiety= شبع) •Substance P: –Major NT in the sensations of pain. 5-Monoxide gases (NO and CO):

They are lipid soluble ; therefore , there receptors are found inside the

cells.

Most of them work through c-GMP.

•Nitric Oxide (NO) vasodilator –Exerts its effects by stimulation of c-GMP.

–Involved in memory and learning.

–Smooth muscle relaxation. •Carbon monoxide (CO) vasodilator –Stimulates production of c-GMP within neurons.

–Promotes odor adaptation in olfactory neurons (olfactory : smell ) .

–May be involved in neuroendocrine regulation in the hypothalamus.

-The secret of getting ahead is getting started-

-Sorry for any mistakes-

-Good luck- <3