Laith Khreisat. Ahmad Ali Massad. Faisal Muhammad

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1 21 Laith Khreisat Ahmad Ali Massad Faisal Muhammad

2 * 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. 1 P a g e

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).

3 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 2 P a g e

4 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: 3 P a g e

5 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 (. مخدر) contraction) that s why it can be used as an anesthetic *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. 4 P a g e

6 -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 5 P a g e

7 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 6 P a g e

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.

as in muscarinic receptors. 2- Monoamines as NT: # They are derivative from tyrosine and tryptophane.

8 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 Norepinephrine -N Serotonin -5-HT 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: 7 P a g e

Kinase A is c-amp dependent protein Kinase ), protein Kinase A then will phosphorylate proteins ( or sometimes may open channels ), phosphorylation of

9 # 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. 8 P a g e

10 * 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: 9 P a g e

11 *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 ( α 2a, α 2b, α 2c ). * 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 10 P a g e

12 ** Platelets : when stimulated they aggregate ( clock together ), this is important for blood clotting. **Antiplatelets ( الدم (مميعات 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) 11 P a g e

13 Gamma-amino-butyric acid (GABA) and glycine: Inhibitory AA 4- polypeptides as NT: CCK: (cholecystokinin ) controls appetite )شبع= satiety ) Promotes satiety following meals. 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 12 P a g e

Neuron types and Neurotransmitters

Neuron types and Neurotransmitters Faisal I. Mohammed. PhD, MD University of Jordan 1 Transmission of Receptor Information to the Brain the larger the nerve fiber diameter the faster the rate of transmission