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Lojayn Salah

Razan Aburumman

Faisal Muhammad

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Note: I tried to include everything that's important from the doctor's slides but you can refer back to

them after studying this sheet..

After you read this sheet you should be able to answer these questions:

- What are the main differences between small Molecules and Neuropeptide

transmitters (NT)?

- What determines the Neurotransmitter of being excitatory or inhibitory?

- What do we mean by agonist and antagonist?

- What are the key steps in the Neurotransmission?

- Giving a clear definition and examples about ionotropic and metabotropic receptors?

Quick Revision about the previous lecture:

There are different types of Neurons (Structural, Multi-Polar, Polar, Bipolar..).

Neurotransmitters are signaling molecules which bind to specific receptor and

alter the behavior of the neuron by a specific action (secretion, contraction,

changing in permeability, etc.)

The properties of the transmitter do not determine its effects on the postsynaptic

cells (I’ll explain this point later on).

“ele sa2al el dr bel emte7an esh y3ni –tetanize- y3tref :PP kol mo7adara bye7ke 3ano”

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Now let’s start

** NT means Neurotransmitter.

- Neurotransmitter also called First messenger signaling molecule.

- Second messenger is a small intracellular molecule that is produced after the first

messenger (hormone or neurotransmitter) binds to its receptor.

→ Some neurotransmitters are generally viewed as “excitatory," making a target neuron

more likely to fire an action potential. Others are generally seen as “inhibitory," making

a target neuron less likely to fire an action potential, so What determines the

neurotransmitter’s effect?

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Simply, if the receptor is coupled to Na+ ion channels the NT is excitatory, but if the

receptor is coupled to K ion channels the NT will be Inhibitory. So the same

neurotransmitter can be both excitatory and inhibitory , it depends on the tissue ‘ if the

receptors are coupled to k or Na channels in that tissue ‘.

The receptor can be found either on the cytoplasmic or the extracellular side of the cell

membrane , it depends on the neurotransmitter ‘ if its water soluble then its receptor Is

on the extracellular side , but if its lipid soluble then its receptor is on the cytoplasmic

side ‘

There are two broad categories of neurotransmitters:

1. Small-molecule neurotransmitters: Which are synthesized locally within the pre-

synaptic terminal, there vesicles can be recycled for the synthesis of these molecules

again, so they are taken up by selective transporters on the membrane of the

terminal. Acetylcholine (ACh), is an example of an excitatory small-molecule

neurotransmitter. Small molecules NT are rapidly acting as compared to slowly

acting neuropeptides, they are also excreted in larger amounts compared to

smaller quantities of neuropeptide

2. Neuropeptides or Neuromodulators: Which are the second category of

neurotransmitters. These messengers differ from small-molecule neurotransmitters

in both size and in the way that they are synthesized. Neuropeptides are synthesized

in the cell body (in the soma) because their synthesis requires peptide bond

formation, then they are transported by axonal transport which is very slow,

sometimes it takes 1 millimeter per day. There vesicles don’t recycle.

** Once they are synthesized (the neurotransmitters), both small molecules and

neuropeptides, are stored in vesicles within the axon terminal until an action potential

arrives, vesicles that store neuropeptides are larger in size and come from Golgi

Apparatus upstairs, in the other hand vesicles that store small-molecule

neurotransmitters are small and it’s formed either in Golgi Apparatus or it might be

recycled.

REMEMBER: NT is released when there is an increase in intracellular Ca++ that enters down

its electrochemical gradient through voltage-gated Ca++ channels when an action potential

reaches these terminals, then NT will bind to specific receptor and produce a certain action.

→ Neurotransmitters should have the same effect on the target cell whether it is added

exogenously or endogenously, for example: if Ach is applied internally or externally to the

cardiac muscles it has to decrease the heart rate.

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→ Neurotransmitters are blocked by some drugs that bind to the same receptor, Blockers

inactivate the action.

→ Classical NT can be removed by specific ways: Diffusion, Enzymes, and Uptake. For

example:

Acetylcholinesterase (AchE) breaks (Ach) into Acetic Acid and Choline, choline will be up

taken and recycled by the pre-synaptic cell for use in the synthesis of more Ach.

Look at the picture below.

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Now, what do we mean by AGONIST and ANTAGONIST?

Agonist: A substance when it binds to receptor, it will produce the same action the NT

produces, before I give you an example, remember that there are two kinds of

receptors for Ach: 1) Nicotinic receptor. 2) Muscarinic receptor. The example is:

* The Agonist substance for Nicotinic receptor is Nicotine, it stimulates the action of Ach

in these receptors.

* The Agonist substance for Muscarinic receptor is Muscarine.

The Antagonist is different, it is a substance that binds to the receptor and inactivate

the neuroreceptor, it blocks the action.

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So drugs are: either receptor agonist (to treat a variety of diseases and disorders when

the original chemical substance is missing or depleted.) or Antagonist (Block the action

of NT or receptor agonist).

Some NT can bind to different

neuroreceptors:

The NT can bind to receptor (A) and

receptor (B), it depends where it’s

found. For instance, Ach can fit one

receptor found in the heart, and other

receptor found in the GI.

- Epinephrine’s receptors “English name

for epinephrine is Adrenaline” are

called: Adrenergic Receptors, there are

two kinds of it

Alpha (α) receptors: there are α1 and α2.

Beta (β) receptors: β1 are found in the heart, and β2 in the lungs.

(An easy way to remember where the Beta (β) receptors are found: β1 receptors are

found in the heart, because there is one heart, β2 in the lungs, because there are two

lungs) “taree2et Dr. Faisal el5orafyeh ;P”.

Specificity of Drugs:

The NT can bind to the receptors A & B...

But for drugs:

Drug A can bind to receptor A only.

Drug B can bind to receptor B only.

* Drugs can be either Agonist or

Antagonist.

- If you want one drug that only blocks the action of epinephrine on the heart, you have

to synthesize a blocker drug for β1.

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Synaptic transmission:

I summarized the steps in a table with pictures, to make it easier to understand:

First step: The neurotransmitter is manufactured by the neuron and stored in vesicles at the axon terminal.

Second step: When the action potential reaches the presynaptic terminal, it causes the Ca++ to move inside → which causes the vesicles to release the neurotransmitter molecules into the synaptic cleft.

Third Step: The neurotransmitter diffuses across the cleft and binds to receptors on the post-synaptic cell.

Forth Step: The activated receptors cause changes in the activity of the post-synaptic neuron.

Fifth step: The neurotransmitter molecules are released from the receptors and diffuse back into the synaptic cleft.

Sixth Step: The Neurotransmitter is re-absorbed by the pre-synaptic neuron. This process is known as Reuptake. There are other “Removal mechanisms", like Diffusion and Enzymes

* If you want to see the colored pictures make sure to open the pdf file.

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** NOTE: In step 2 → The action potential causes the opening of Ca++ voltage gated

channels, Ca++ will move for outside to inside according its electrochemical gradient

(The concentration of Ca++ extracellularly = 10-3 M , and intracellularly = 10-7M).

REMEMBER:

- We said that peripheral nervous system contains different synaptic vesicles, vesicles

for neuropeptides (neuromodulators) come from SOMA, and vesicles for small

molecules come from pre-synaptic terminal.

- We said that only the vesicles of “small molecules rapidly acting” can be recycled.

- Vesicles of “small molecules rapidly acting” can secrete large amount of NT, while

vesicles of “neuropeptides (neuromodulators)” secrete smaller amount.

- The important difference between two kinds of synaptic vesicles is DURATION; small

molecules act rapidly but their duration is short, in the other hand, neuropeptides act

slowly, but their duration is long.

** Now I will tell you that each neuron should have only one small molecule

neurotransmitter, but it might contain more than one neuropeptide, this is called Co-

existence.

-The NT co-exist: Neuropeptides are found in the same Neuron that contains vesicles of

Classical NT-small molecules- “Dale Principle”.

Neuropeptides/Neuromodulators: They are not secreted alone, usually "co-secrete"

with small molecules rapidly acting neurotransmitters. HOW? Well, it depends on the

stimulus:

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→ Sometimes low frequency stimulus gives just small molecules.

→ High frequency stimulus secretes both small molecules and neuropeptides

(neuromodulators).

Important Question: Do we consider Epinephrine and Norepinephrine as two different

classical neurotransmitters??

NO, E and NE are one neurotransmitter and could be found in the same neuron.

*Neuromodulators: They modulate the action of the neurotransmitter in term of

prolongation of the action.

*Classical NT (small molecules rapidly acting NT): causes fast action.

We have 2 kinds of receptors for Neuroreceptors:

Before I give the information look at the picture below and try to figure out the 2 kinds

and the differences between them ↓

1) Ionotropic receptors:

They are group of transmembrane ion channels that open or close in response to the

binding of a chemical messenger (Transmitters), this kind of response is very fast but its

duration is shorter, Ionotropic Channels are for anions and cations. Ionotropic receptors

are not open always.

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Ionotropic receptors depend mainly on the presence or absence of NT, for example:

- NT bind to the channels → they open. (ACTIVATION)

- NT is broken down (by acetylcholinesterase for example) → the channels close.

(INACTVATION)

** Important NOTE: There is a huge deference between inotropic and ionotropic,

inotropic refers to the contraction of the heart muscles. “Ma t5arbeto benhom daroori”

2) Metabotropic receptors:

They are a subtype of membrane receptors that do not form an ion channel (they do

not have a channel that open and close) instead, they use

signal transduction mechanisms, often G proteins, to activate a series of intracellular

events using second messenger chemicals. They are slower than ionotropic.

As soon as a ligand binds the metabotropic receptor, the receptor “activates” the G-

Protein (it basically changes the G-Protein). Once activated, the G-protein itself goes on

and activates another molecule. This new molecule is called a “secondary messenger.”

What is G-Protein?

It is made of 3 subunits (Gα , Gβ ,Gγ ) which are connected together by GDP “Guanine Di

Phosphate”

When NT comes, Gα become activated and it can undergoes two mechanisms:

1) Direct Control (NOT second messenger mechanism): Here, G protein is bound to a

channel. G alpha subunit dissociate from beta and gamma subunits, then it (alpha

subunit) opens or closes an ion channel. It's faster than the second messenger

mechanism and a little bit slower than ionotropic channels.

2) Second Messenger Mechanism: Gα activates AC to convert ATP to cAMP, then cAMP

activates PKA (protein kinase A), as any kinase protein it uses ATP in order to

phosphorylate proteins which might open the channel, in general phosphorylation will

change the channel’s permeability . Note that the mechanism is slow “slower than the

direct control”, but it's not the slowest! The slowest mechanisms are those that affect

genes. Genes produce proteins and these proteins could be channels.

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NOTE: Second messenger is not always c-AMP:

- Maybe the nearby enzyme would be Guanylyl cyclase which converts GTP into c-GMP,

so here c-GMP would be the second messenger.

- Or maybe binding the NT to the receptor will activate Phospholipase C which cleave

one of the fatty acids in the phospholipid and it (the phospholipid) will be called

“Diacylglycerol” .The other product is called: IP3 “inositol tri phosphate” goes down to

the ER and causes the release of Ca++. Diacylglycerol and Ca++ work as second messenger

for another protein kinase which is called “Protein Kinase C”

** So second messenger could be: c-AMP , c-GMP , Ca++ , Diacylglycerol .. etc.)

Now How can we inactivate the NT ?

Reuptake by presynaptic terminal

Uptake by glial cells

Enzymatic degradation (The enzymes are formed in the postsynaptic membrane).

Presynaptic receptor

Diffusion

Combination of above.

Some Important Transmitters:

1. Acetylcholine (Ach) 3. Amino Acids

2. Monoamines 4.Polypeptides"Neuromodulators"

5. Monoxide Gases (NO and CO).

1) Acetylcholine (Ach):

It’s a neurotransmitter which is found in the presynaptic terminal, It’s formed from Choline+ Acetyl CoA. “Acetyl CoA comes from metabolic activities”, It's broken down by acetylcholinesterase into "choline" + "Acetate or Acetic acid".

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- Choline mostly will reuptake by secondary active pathway called Choline-Sodium co-transport, it uses the energy of sodium gradient.

REMEMBER: Neuropeptides can't be reused.

Ach Distribution:

→ We said when we talked about peripheral nervous system that the only NT that found between nerves and skeletal muscle “neuro-muscular junctions” is ACH.

→Ach is also found in the autonomic nervous system:

* Ach is the NT at the preganglionic neuron in both sympathetic and parasympathetic. * Ach is the NT at the postganglionic neuron of the parasympathetic mainly.

Ach Receptors: (Cholinergic Receptors):

Nicotinic Receptors: which are found in the autonomic ganglia of sympathetic and parasympathetic nervous systems, and at the neuromuscular junction and in the adrenal medulla. And as mentioned before it is stimulated by Nicotine (agonist), and blocked by Curare (antagonist).

LOCATION: (N1) is found in: autonomic Ganglia (sympathetic and parasympathetic) also N1 is found in Hormone producing cells in Adrenal medulla 2.

(N2): Found in skeletal muscles. (Motor endplate)

Muscarinic Receptors: which are found in the effector organ, and are stimulated by Muscarine (agonist), and blocked by atropine (antagonist).

(M1) receptor: is found in the smooth muscles, it’s excitatory; because it’s bounded to Na ion channels. HOW it works?

Activation of Phospholipase C (PLC) → acts on membrane phospholipids → Inositol triphosphate (IP3) and diacylglycerol (DAG) → ↑ Ca++ & Protein Kinase C (PKC) → Depolarization → Excitation → decrease K+ conductance.

(M2) receptor: it’s found in cardiac muscle cells and in the GI, it’s inhibitory; because it’s bounded to K ion channels. HOW it works?

Inhibition of Adenylyl Cyclase (AC) → ↓ c-AMP & ↓ Ca++ conductance →↑ K+

conductance → inhibition.

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** Ach receptor is excitatory (in the GI) and inhibitory (in the Heart).

Cholinergic Agonists:

1) Direct: which works on the receptor → Muscarine and Nicotine.

2) Indirect: which causes prolongation of the action of Ach → Acetylcholinesterase inhibitors.

In the next lecture we will continue our talk about the other important transmitters.

The wind cannot defeat a tree with strong roots.

End Of Sheet <3

Don’t Hesitate to message me on fb if you have any comment or question ..

Lojayn Salah send her regards and leave you here

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