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Neurotransmitter and Its Synapses -Ppt

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Neurotransmitters and Synapses
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Page 1: Neurotransmitter and Its Synapses -Ppt

Neurotransmitters and Synapses

Page 2: Neurotransmitter and Its Synapses -Ppt

2

NEUROTRANSMITTERS

DEFINITION: Are chemical transducers which are released by electrical impulse into the synaptic cleft from presynaptic membrane from synaptic vesicles. It then diffuse to the postsynaptic membrane and react and activate the receptors present leading to initiation of new electrical signals.

Page 3: Neurotransmitter and Its Synapses -Ppt

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Discovery of neurotransmitters

• Loewi, 1921

• frog hearts in saline solution

• Stimulation of vagus nerve results in lower heart rate

– gave long vagal nerve stimulation

• Heart #2:

– Exposed to saline solution from heart #1

– Slowed heart rate

• Conclusion: Neurotransmission is

chemical

– nerve releases chemical that can influence other cells

Fig 8.1, Zigmond “Fundamental Neuroscience”

Page 4: Neurotransmitter and Its Synapses -Ppt

Neurotransmitters

• substances that mediate chemical

signaling between neurons.

• criteria for a substance to be

considered a neurotransmitter.

– they must be demonstrated to be present

in the presynaptic terminal

– they must be synthesize by the presynaptic

cell.

– they should be released on depolarization

of the terminal

– there should be specific receptors for them

on the postsynaptic membrane or other

sites outside the synapse

Page 5: Neurotransmitter and Its Synapses -Ppt

• A junction that mediates information transfer from one neuron: – To another neuron

• Called neuro-synapses or just synapse

– To an effector cell • Neuromuscular synapse if muscle involved

• Neuroglandular synapse if gland involve

• Presynaptic neuron – conducts impulses toward the synapse

• Postsynaptic neuron – transmits impulses away from the synapse

• Two major types: – Electrical synapses

– Chemical synapses

Synapses

Page 6: Neurotransmitter and Its Synapses -Ppt

Synapses

Figure 11.17

1. Axodendritic synapse 2. Axosomatic synapse 3. Axoaxonic synapse

Page 7: Neurotransmitter and Its Synapses -Ppt

Electrical Synapses • Pre- and postsynaptic neurons

joined by gap junctions

– allow local current to flow between adjacent cells. Connexons: protein tubes in cell membrane.

• Rare in CNS or PNS

• Found in cardiac muscle and many types of smooth muscle. Action potential of one cell causes action potential in next cell, almost as if the tissue were one cell.

• Important where contractile activity among a group of cells important.

Page 8: Neurotransmitter and Its Synapses -Ppt

Chemical Synapses

• Most common type

• Cells not directly coupled as in electrical synapses

• Components – Presynaptic terminal

– Synaptic cleft

– Postsynaptic membrane (PSM)

• Chemical neurotransmitters (NT‟s) released by presynaptic neuron

• NT binds to receptor on PSM

Page 9: Neurotransmitter and Its Synapses -Ppt

Chemical Synapse Events at a chemical synapse 1. Arrival of action potential on presynaptic

neuron opens volage-gated Ca++ channels. 2. Ca++ influx into presynaptic term. 3. Ca++ acts as intracellular messenger stimulating synaptic vesicles to fuse with membrane and release NT via exocytosis. 4. Ca++ removed from synaptic knob by mitochondria or calcium-pumps. 5. NT diffuses across synaptic cleft and binds to receptor on postsynaptic membran 6. Receptor changes shape of ion channel opening it and changing membrane

potential 7. NT is quickly destroyed by enzymes or taken back up by astrocytes or presynaptic membrane. Note: For each nerve impulse reaching the

presynaptic terminal, about 300 vesicles are emptied into the cleft. Each vesicle contains about 3000 molecules.

Page 10: Neurotransmitter and Its Synapses -Ppt

Types of Synaptic Transmission

Electrical

• occurs in gap junction

• by simple electrical

coupling

• usually bidirectional

• fast transmission

• (-) synaptic delay

Chemical

• occurs in synaptic cleft

• utilized a chemical

intermediaries

(neurotransmitter)

• unidirectional

• slow transmission

• (+) synaptic delay

Page 11: Neurotransmitter and Its Synapses -Ppt

Synaptic Delay

• 0.2-0.5 msec delay between arrival of AP at synaptic knob and effect on PSM

– Reflects time involved in Ca++ influx and NT release

– While not a long time, its cumulative synaptic delay along a chain of neurons may become important.

– Thus, reflexes important for survival have only a few synapses

Synaptic Fatigue • Under intensive stimulation, resysnthesis and transport of

recycled NT may be unable to keep pace with demand for NT

• Synapse remains inactive until NT has been replenished

Page 12: Neurotransmitter and Its Synapses -Ppt

Neurotransmitters

• more than 100 have been identified as potential

neurotransmitters or potential qualifiers.

• three major categories

– small molecule transmitters

• acetylcholine

• amino acids

• biogenic amines

• purines

– peptides

– gaseous transmitters

Page 13: Neurotransmitter and Its Synapses -Ppt

Neurotransmitters

• contained in synaptic vesicles.

• three kinds of synaptic vesicles

– small clear synaptic vesicle

• acethylcholine, glycine, GABA and glutamate

– small vesicle with dense core

• catecholamines

– large vesicle with dense core

• neuropeptides

Page 14: Neurotransmitter and Its Synapses -Ppt

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Fate of neurotransmitters

1. It is consumed ( broken down or used up) at postsynaptic membrane leading to action potential generation.

2. Degraded by enzymes present in synaptic cleft.

3. Reuptake mechanism( reutilization) this is the most common fate.

Page 15: Neurotransmitter and Its Synapses -Ppt

Removal of Neurotransmitter from Synaptic Cleft

• Method depends on neurotransmitter

• ACh: acetylcholinesterase splits ACh into acetic acid and choline. Choline recycled within presynaptic neuron.

• Norepinephrine: recycled within presynaptic neuron or diffuses away from synapse. Enzyme is monoamine oxidase (MAO). Absorbed into circulation, broken down in liver.

Page 16: Neurotransmitter and Its Synapses -Ppt

Receptor Molecules and Neurotransmitters

• Neurotransmitter only "fits" in one receptor.

• Not all cells have receptors.

• Neurotransmitters are commonly classified as excitatory or inhibitory.

• Classification is useful but not precise. For example: – ACh is stimulatory at neuromuscular junctions (skeletal)

– ACh is inhibitory at neuromuscular junction of the heart

• Therefore, effect of NT on PSM depends on the type of receptor, and not nature of the neurotransmitter

• Some neurotransmitters (norepinephrine) attach to the presynaptic terminal as well as postsynaptic and then inhibit the release of more neurotransmitter.

Page 17: Neurotransmitter and Its Synapses -Ppt

• NT affects the postsynaptic membrane potential

• Effect depends on:

– The amount of neurotransmitter released

– The amount of time the neurotransmitter is bound to receptors

• The two types of postsynaptic potentials are:

– EPSP – excitatory postsynaptic potentials

– IPSP – inhibitory postsynaptic potentials

Postsynaptic Potentials

Page 18: Neurotransmitter and Its Synapses -Ppt

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Types of responses on postsynaptic membrane

• Excitatory postsynaptic potential (EPSPs)

It is caused by depolarization.

• Inhibitory Postsynaptic potential (IPSPs)

It is caused by hyperpolarization.

Page 19: Neurotransmitter and Its Synapses -Ppt

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Fast & Slow Postsynaptic potentials

• Fast EPSPs & IPSPs work through ligand gated ion channels.eg. Nicotinic receptors(at the level of neuromuscular junction)

• Slow EPSPs & IPSPs are produced by multi step process involving G protein eg. Muscarinic receptors ( at the level of autonomic gangila)

Page 20: Neurotransmitter and Its Synapses -Ppt

• EPSPs are graded potentials that can initiate an action potential in an axon – Use only chemically gated channels

• Postsynaptic membranes do not generate action potentials

• But, EPSPs bring the RMP closer to threshold and therefore closer to an action potential

Excitatory Postsynaptic Potentials

Page 21: Neurotransmitter and Its Synapses -Ppt

• Neurotransmitter binding to a receptor at inhibitory synapses: – Causes the membrane to become more

permeable to potassium and chloride ions

– Leaves the charge on the inner surface more negative (flow of K+ out of the cytosol makes the interior more negative relative to the exterior of the membrane

– Reduces the postsynaptic neuron‟s ability to produce an action potential

Inhibitory Synapses and IPSPs

Page 22: Neurotransmitter and Its Synapses -Ppt

• A single EPSP cannot induce an action potential

• EPSPs must summate temporally or spatially to induce an action potential

• Temporal summation – one presynaptic neuron transmits impulses in rapid-fire order

• Spatial summation – postsynaptic neuron is stimulated by a large number of presynaptic neurons at the same time

• IPSPs can also summate with EPSPs, canceling each other out

Summation

Page 23: Neurotransmitter and Its Synapses -Ppt

Summation

Figure 11.21

Page 24: Neurotransmitter and Its Synapses -Ppt
Page 25: Neurotransmitter and Its Synapses -Ppt

• Chemicals used for neuronal communication with the body and the brain

• 100 different neurotransmitters have been identified

• Classified chemically and functionally

– Chemically:

• ACh, Biogenic amines, Peptides

– Functionally:

• Excitatory or inhibitory

• Direct/Ionotropic (open ion channels)

• Indirect/metabotropic (activate G-proteins) that create a metabolic change in cell

Neurotransmitters

Page 26: Neurotransmitter and Its Synapses -Ppt

• Direct: neurotransmitters that open ion channels – Promote rapid responses

– Examples: ACh and amino acids

• Indirect: neurotransmitters that act through second messengers – Promote long-lasting effects

– Examples: biogenic amines, peptides, and dissolved gases

Neurotransmitter Receptor Mechanisms

Page 27: Neurotransmitter and Its Synapses -Ppt

• Composed of integral membrane protein

• Mediate direct neurotransmitter action

• Action is immediate, brief, simple, and highly localized

• Ligand binds the receptor, and ions enter the cells

• Excitatory receptors depolarize membranes

• Inhibitory receptors hyperpolarize membranes

Channel-Linked Receptors

Page 28: Neurotransmitter and Its Synapses -Ppt

Channel-Linked Receptors

Figure 11.23a

Page 29: Neurotransmitter and Its Synapses -Ppt

• Responses are indirect, slow, complex, prolonged, and often diffuse

• These receptors are transmembrane protein complexes

• Examples: muscarinic ACh receptors, neuropeptides, and those that bind biogenic amines

G Protein-Linked Receptors

Page 30: Neurotransmitter and Its Synapses -Ppt

• Neurotransmitter binds to G protein-linked receptor

• G protein is activated and GTP is hydrolyzed to GDP

• The activated G protein complex activates adenylate cyclase

• Adenylate cyclase catalyzes the formation of cAMP from ATP

• cAMP, a second messenger, brings about various cellular responses

G Protein-Linked Receptors: Mechanism

Page 31: Neurotransmitter and Its Synapses -Ppt

G Protein-Linked Receptors: Mechanism

Figure 11.23b

Page 32: Neurotransmitter and Its Synapses -Ppt

• G protein-linked receptors activate intracellular second messengers including Ca2+, cGMP, and cAMP

• Second messengers:

– Open or close ion channels

– Activate kinase enzymes (phosphorylation rxn‟s)

– Phosphorylate channel proteins

– Activate genes and induce protein synthesis!!

G Protein-Linked Receptors: Effects

Page 33: Neurotransmitter and Its Synapses -Ppt

• Acetylcholine (ACh)

• Biogenic amines

• Amino acids

• Peptides

• Novel messengers: ATP and dissolved gases NO and CO

Chemical Neurotransmitters

Page 34: Neurotransmitter and Its Synapses -Ppt

• First neurotransmitter identified (by Otto Loewi) and best understood

• Synthesized and enclosed in synaptic vesicles

• Degraded by the enzyme acetylcholinesterase (AChE)

• Released by cholinergic neurons:

– All skeletal muscle motor neurons • Anterior horn motor neuron (= Lower motor neuron)

– Some neurons in the autonomic nervous system • All ANS preganglionic neurons (parasym. and sympathetic)

• All parasympathetic postganglionic neurons stimulating smooth muscle, cardiac muscle, and glands

• Symp. postganglionic neurons stimulating sweat glands

• Ach binds to cholinergic receptors known as nicotinic or muscarinic receptors

Neurotransmitters: Acetylcholine

Page 35: Neurotransmitter and Its Synapses -Ppt

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Nicotinic Muscarinic

1 Found at:

i. Neuromuscular junction of

skeletal muscle

ii. Postganglionic neurons of

parasympathetic nervous

system.

iii. Ventral tegmental area.

i. Glands

ii. Neuromuscular junctions of

cardiac and smooth muscle.

iii. Postganglionic neurons of

sympathetic nervous system.

2 Agonist Nicotine Muscarine ( a toxin produced by

certain mushroom)

3 Antagonist Curare ( paralyses skeletal

muscle)

Atropine

Acetyl Choline Receptors

Page 36: Neurotransmitter and Its Synapses -Ppt

Comparison of Somatic and Autonomic Systems

Figure 14.2

Page 37: Neurotransmitter and Its Synapses -Ppt

Cholinergic Receptors: Bind ACh

• Nicotinic receptors

- Are ion channels (rapid acting)

- On sarcolemma of skeletal muscle fibers

- On dendrites and cell bodies of ALL postganglionic

neurons of the ANS

- Excitatory (open Na+ channels fast EPSP)

• Muscarinic receptor

- Are G-protein couple receptors (complex intracellular

functions)

- On all parasympathetic target organs (cardiac and smooth muscle)

- Are excitatory in most cases; inhibitory in others

Page 38: Neurotransmitter and Its Synapses -Ppt

Acetylcholine

• Effects prolonged (leading to tetanic muscle spasms

and neural “frying”) by nerve gas and organophosphate insecticides (Malathion).

• ACH receptors destroyed by patients own antibodies in myasthenia gravis

• Binding to receptors inhibited by curare (a muscle paralytic agent

– blowdarts in south American tribes and some snake venoms.

Page 39: Neurotransmitter and Its Synapses -Ppt

• Include:

– Catecholamines – dopamine, norepinephrine (NE), and epinephrine (EP)

– Indolamines – serotonin and histamine

• Broadly distributed in the brain

• Cathecholamine are important sympathetic NTs

• Play roles in emotional behaviors and our biological clock

Neurotransmitters: Monoamines/Biogenic Amines

Page 40: Neurotransmitter and Its Synapses -Ppt

Synthesis of Catecholamines

• AA tyrosine is parent cpd

• Enzymes present in the cell determine length of biosynthetic pathway

• Norepinephrine and dopamine are synthe-sized in axonal terminals

• Epinephrine is released by the adrenal medulla as a hormone

Figure 11.22

Page 41: Neurotransmitter and Its Synapses -Ppt

41 MAO=monoamine oxidase ,COMT=catechole-o-methyle-transferase

Page 42: Neurotransmitter and Its Synapses -Ppt

BIOGENIC AMINES: Norepinephrine

• Norepinephrine (aka Noradrenaline) – Main NT of the sympathetic branch of autonomic nervous system

– Binds to adrenergic receptors ( or -many subtypes, 1, 2, etc)

– Excitatory or inhibitory depending on receptor type bound

– Very important role in attention and arousal - an organisms vigilance

– Also released by adrenal medulla as a hormone

– “Feeling good” NT

• Clinical Importance – Thought to be involved in etiology of some bipolar affective disorders

• Removal from synapse blocked by antidepressants and cocaine

• Levels lowers in depressed pts. and higher in manic phase of bipolar dis.

– Release enhanced by amphetamines

Page 43: Neurotransmitter and Its Synapses -Ppt

BIOGENIC AMINES: Dopamine

• Dopamine – Binds to dopaminergic receptors of substantia nigra of midbrain and hypothalamus

– Involved in important physiology functions including:

• Motor control

• Coordinating autonomic functions

• Regulating hormone release

• Motivational behavior and reward; i.e., a “feeling good” NT

– Hypothesized to be at the heart of the mechanisms of ALL addictive-

drugs and behaviors. For example,

• Release enhanced by amphetamines

• Reuptake blocked by cocaine

– Deficient in Parkinson‟s disease

– Receptor abnormalities have been linked to development of schizo-

phrenia

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Page 45: Neurotransmitter and Its Synapses -Ppt

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Page 46: Neurotransmitter and Its Synapses -Ppt

Small Molecule Transmitters

• Biogenic Amines

– they have roles outside the nervous system as hormones.

– include

• catecholamines - epinephrine (adrenaline),

norepinephrine (noradrenaline) and dopamine

– from amino acid tyrosine

• serotonin (5 – HT)

– from amino acid tryptophan

• histamine

– from histidine

Page 47: Neurotransmitter and Its Synapses -Ppt

Biogenic Amines: Serotonin (5-HT)

• Synthesized from the amino acid tryptophan

– Since tryptophan not synthesized in humans, its levels available for synthesis of serotonin are dependent on diet.

• Diets high in tryptophan can markedly elevate serotonin levels

• May play a role in sleep, appetite, and regulation of moods (aggression)

• Low 5-HT levels associated with increased aggressiveness and risk taking

• Acts in a pathway that monitors carbohydrate intake, acting as a negative regulator of motivation to ingest carbohydrate

– Has led to the use of SSRIs (see below) as obesity pills (fenfluramine)

• Drugs that block its uptake relieve anxiety and depression and aggression

– SSRI‟s = selective serotonin reuptake inhibitors

– Include drugs such as Prozac, Celexa, Lexapro, Zoloft

• Ecstasy targets serotonin receptors

Page 48: Neurotransmitter and Its Synapses -Ppt

48

Formation of serotonin =5-HT Hydroxy tryptamine HIAA=hydroxyindoleacetic acid

Page 49: Neurotransmitter and Its Synapses -Ppt

49

Histamine

• Histamine forming cells are in posterior hypothalamus also found in gastric mucosa and in mast cells.

• Formed by decarboxylation of amino acid histidine with the help of enzyme histaminase.

• Three known types of histamine receptors in found e.g. H1, H2, H3.

• H3 receptors are presynaptic. Its function in brain is not very certain. Its main function is that it is excitatory.

Page 50: Neurotransmitter and Its Synapses -Ppt

BIOSYNTHESIS

OF

CATECHOLAMINES

Page 51: Neurotransmitter and Its Synapses -Ppt

Small Molecule Transmitters

• Biogenic Amines

– involved in setting the level of arousal (sleep and waking),

attention and mood.

– important in homoestatic functions (ANS) and motor

system.

• Catecholamines (NE and E)

– from the brainstem nuclei (locus ceruleus and nucleus subceruleus)

and postganglionic sympathetic cells.

• Serotonin (from midline of the brainstem (raphe nuclei)

• Histamine (from the hypothalamus)

• Dopamine (from substancia nigra and tegmental area)

Page 52: Neurotransmitter and Its Synapses -Ppt

Small Molecule Transmitters

• Purines --- ATP

– has potential to act as a transmitter or co-

transmitter in the CNS and PNS.

– has receptors coupled to an ion channel.

– can modify the action of other transmitters

with which it is co-released (NE, 5-HT etc)

Page 53: Neurotransmitter and Its Synapses -Ppt

• Include:

– GABA – Gamma ()-aminobutyric acid

– Glycine

– Aspartate

– Glutamate

• Found only in the CNS

Neurotransmitters: Amino Acids

Page 54: Neurotransmitter and Its Synapses -Ppt

Small Molecule Transmitters

• Amino acids --- Glutamate

– major excitatory CNS neurotransmitter

– present in all cells and has a key role in

multiple metabolic pathways.

– a precursor to GABA

– a potent neurotoxin at high concentrations

Page 55: Neurotransmitter and Its Synapses -Ppt

55

Glutamic acid • It is the most commonly found neurotransmitter

in the brain. • It is always excitatory. • Glutamate is formed during Kreb‟s cycle for α –

ketoglutarate. • Glutamate is carried into astrocytes where it is

converted to glutamine and passed on to glutaminergic neurones.

• Glutamate is neurotoxic while glutamine is not. • There are two types of receptors e.g.

metabotropic and iontropic receptors.

Page 56: Neurotransmitter and Its Synapses -Ppt

Amino Acid Neurotransmitters • Excitatory Amino Acids

1. Glutamate • Indirect action via G proteins and 2nd messengers

• Direct action -- opens Ca++ channels (ionotropic)

– NMDA receptors (have a high permeability to Ca++)

• Widespread in brain where it represents the major excitatory neurotransmitter

• Important in learning and memory! • Highly toxic to neurons when present for extended

periods - “Stroke NT” -excessive release produces

excitotoxicity: neurons literally stimulated to death; most commonly caused by ischemia due to stroke (Ouch!) • Aids tumor advance when released by gliomas (ouch!)

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57

NMDA =N methyl-D-aspartate receptors, when glutamate & glycine bind to receptor ion channels open, Mg block channels

Page 58: Neurotransmitter and Its Synapses -Ppt

58

Page 59: Neurotransmitter and Its Synapses -Ppt

Small Molecule Transmitters

• Amino acids --- Glycine

– an inhibitory neurotransmitter in a much

more restricted territories.

– predominantly found in spinal cord and

also present in lower brainstem,

cerebellum and the retina.

– acts as a co-transmitter at NMDA-type

glutamate receptors.

Page 60: Neurotransmitter and Its Synapses -Ppt

60

Glycine

• It is simplest of all aminoacids, consisting of amino group and a carboxyl group attached to a carbon atom

C H3 N+

Coo-

H+

H+

Page 61: Neurotransmitter and Its Synapses -Ppt

61

• Its an inhibitory neurotransmitter.

• It binds to a receptor which makes the post synaptic membrane more permeable to Cl- Ion and cause hyperpolarization (inhibition).

• The glycine receptor is primarily found in the ventral part of the spinal cord.

• Strychnine is glycine antagonist.

Glycine……..

Page 62: Neurotransmitter and Its Synapses -Ppt

62

Gamma Aminobutyric acid (GABA)

• It is one of the inhibitory neurotransmitter of CNS and is also found in retina.

• It is formed by decarboxylation of glutamate. • The enzyme that catalyzes this reaction is

glutamate decarboxylase(GAD) • There are three types of GABA receptors e.g.

GABAA B & C.

• GABA A & B receptors are widely distributed in CNS.

• GABAC are found in retina only. • GABA B are metabotropic (G-protein) in

function.

Page 63: Neurotransmitter and Its Synapses -Ppt

Amino Acids

Inhibitory Amino Acids 1. GABA (Gamma aminobutyric acid)

• Direct or indirect action (depending on type of receptor

• Main inhibitory neurotransmitter in the brain - Selectively permeable to Cl- (hyperpolarizes memb.)

• Cerebral cortex, cerebellum, interneurons throughout brain and spinal cord

• Inhibitory effects augmented by alcohol and benzodiazepines (antianxiety drugs like Valium and Librium) and barbiturates - these drugs increase the number of GABA receptors

and thus enhance the inhibitory activity of GABA • Decreased GABA inhibition amy lead to epilepsy

Page 64: Neurotransmitter and Its Synapses -Ppt

64

Neurotransmitter Postsynaptic

effect Derived from

Site of

synthesis

Postsynaptic

receptor Fate Functions

1.Acetyl choline

(Ach)

Excitatory Acetyl co-A +

Choline

Cholinergic

nerve endings

Cholinergic

pathways of

brainstem

1.Nicotinic

2.Muscarinic

Broken by acetyl

cholinesterase

Cognitive functions

e.g. memory

Peripheral action e.g.

cardiovascular

system

2. Catecholamines

i. Epinephrine

(adrenaline)

Excitatory in

some but

inhibitory in

other

Tyrosine

produced in

liver from

phenylalanine

Adrenal

medulla and

some CNS

cells

Excites both

alpha α &

beta β

receptors

1.Catabolized to

inactive product

through COMT &

MAO in liver

2.Reuptake into

adrenergic nerve

endings

3.Diffusion away

from nerve

endings to body

fluid

For details refer

ANS. e.g. fight or

flight, on heart,

BP, gastrointestinal

activity etc.

Norepinehrine

controls attention &

arousal.

ii.Norepinephrine Excitatory Tyrosine, found

in pons.

Reticular

formation, locus

coerules,

thalamus, mid-

brain

Begins inside

axoplasm of

adrenergic

nerve ending is

completed

inside the

secretary

vesicles

α1 α2

β1 β2

iii. Dopamine Excitatory Tyrosine CNS,

concentrated in

basal ganglia

and dopamine

pathways e.g.

nigrostriatal,

mesocorticolim

bic and tubero-

hypophyseal

pathway

D1 to D5

receptor

Same as above Decreased dopamine

in parkinson’s

disease.

Increased dopamine

concentration causes

schizophrenia

Page 65: Neurotransmitter and Its Synapses -Ppt

65

Neurotransmitter Postsynaptic

effect Derived from

Site of

synthesis

Postsynaptic

receptor Fate Functions

6. Aspartate Excitatory Acidic amines Spinal cord Spinal cord Aspartate & Glycine form an excitatory /

inhibitory pair in the ventral spinal cord

7. Gama amino

butyric

acid(GABA)

Major

inhibitory

mediator

Decarboxylation

of glutamate by

glutamate

decarboxylase

(GAD) by

GABAergic

neuron.

CNS

GABA – A

increases the Cl - conductance,

GABA – B is

metabotropic

works with G –

protein GABA

transaminase

catalyzes.

GABA – C

found

exclusively in

the retina.

Metabolized by

transamination to

succinate in the citric

acid cycle.

GABA – A causes

hyperpolarization

(inhibition)

Anxiolytic drugs like

benzodiazepine cause

increase in Cl- entry

into the cell & cause

soothing effects.

GABA – B cause

increase conductance

of K+ into the cell.

8. Glycine Inhibitory

Is simple amino

acid having

amino group and

a carboxyl group

attached to a

carbon atom

Spinal cord

Glycine receptor

makes

postsynaptic

membrane more

permeable to Cl-

ion.

Deactivated in the

synapse by simple

process of

reabsorbtion by active

transport back into

the presynaptic

membrane

Glycine is inhibitory

transmitted found in

the ventral spinal

cord. It is inhibitory

transmitter to

Renshaw cells.

Page 66: Neurotransmitter and Its Synapses -Ppt

Peptides • more than 100 neuropeptides have been identified.

• co-released with classic neurotransmitters but can

function as a sole or primary neurotransmitter at a

synapse.

• synthesized in the cell body and transported to the

axon

• examples

– hypothalamic hormones, neuropeptide Y,

opioids, tachykinins, etc.

Page 67: Neurotransmitter and Its Synapses -Ppt

• Neuropeptide receptors are all G-protein linked – Alter levels of intracellular second messengers

• Include: – Substance P – mediator of pain signals

– Neuropeptide Y - stimulates appetite and food intake

– Beta endorphin, dynorphin, and enkephalins

– Opiods: include • Endorphins, Enkephalins, Dynorphin

• Act as natural opiates, reducing our perception of pain

• Found in higher concentrations in marathoners and women who have just delivered

– Bind to the same receptors as opiates and morphine

Neurotransmitters: Peptides

Page 68: Neurotransmitter and Its Synapses -Ppt

Gas Neurotransmitters

• neither packed into synaptic vesicles nor released

by exocytosis.

• synthesis is triggered by depolarization

• highly permeant and simply diffuse from the nerve

terminal to the neighboring cells.

• destroyed by diffusion or binding to superoxide

anions or various scavenger proteins.

• do not bind to a receptor

• examples: NO (inhibitory transmitter) and CO

Page 69: Neurotransmitter and Its Synapses -Ppt

• Nitric oxide (NO) – Same substance produced by sublingual nitroglycerin

produces to increase vasodilation in relief of angina

– A short-lived toxic gas; diffuses through post-synaptic membrane to bind with intracellular receptor (guanynyl cyclase)

• Is a free radical and therefore highly reactive compound

– Do not confuse with „laughing gas‟ (nitrous oxide)

– Is involved in learning and memory

– Important in control of blood flow through cerebro-vasculature

– Some types of male impotence treated by stimulating NO release (Viagra)

• Viagra NO release smooth muscle relaxation increased blood flow erection

• Can‟t be taken when other pills to dilate coronary b.v. taken

Neurotransmitters: Novel Messengers

Page 70: Neurotransmitter and Its Synapses -Ppt

Destruction of Small molecule Transmitters

• Acetylcholine

– enzymatic hydrolysis by acetylcholenesterase

– reuptake of choline at the presynaptic terminal

by Na+ symporter.

• Amino acid

– Reuptake into the neurons and glial cells

• Glutamate - Na+ - K+ transporter

• GABA - Na+– Cl- transporter

• Glycine - Na+– Cl- transporter

Page 71: Neurotransmitter and Its Synapses -Ppt

Destruction of Small molecule Transmitters

• biogenic amines

– Reuptake into the neuron and glial cells

• Na+– Cl- transporter

– enzymatic hydrolysis by MOA and COMT

• purines

– hydrolyzed by ATPase

Page 72: Neurotransmitter and Its Synapses -Ppt
Page 73: Neurotransmitter and Its Synapses -Ppt

Neurotransmitter Receptors

• small molecule transmitters

– biogenic amines (metabotropic receptors except 5 –

HT3)

• catecholamines (α1, α2, β1, β2, and β3)

• histamine (H1 and H2 )

• dopamine (D1, D2, D3, D4, and D5)

• serotonin (5HT1, 5HT2, 5HT3 and 5HT4)

– purines

• ionotropic (P2X) and metabotropic (P2Y)

• peptides

– neuropeptide receptors

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MEDICAL PHYSIOLOGY 23TH EDITION by Ganong

RELESE OF NEUROTRANSMITERS

Page 75: Neurotransmitter and Its Synapses -Ppt

MEDICAL PHYSIOLOGY 23TH EDITION by Ganong

RELESE OF NEUROTRANSMITERS

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• Two classifications: excitatory and inhibitory

– Excitatory neurotransmitters cause depolarizations (e.g., glutamate)

– Inhibitory neurotransmitters cause hyperpolarizations (e.g., GABA)

Functional Classification of Neurotransmitters

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• Some neurotransmitters have both excitatory and inhibitory effects – Determined by the receptor type of the

postsynaptic neuron

– Example: acetylcholine • Excitatory at neuromuscular junctions with

skeletal muscle (nicotinic receptor)

• Inhibitory in cardiac muscle (muscarinic receptor)

Functional Classification of Neurotransmitters

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Alzheimer’s Disease

• a form of dementia in which

memory function is

gradually and progressively

lost

• due to degeneration of

cholinergic neurons in the

basal forebrain areas,

neocortex, hippocampus and

amygdala (implicated in

memory function).

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RECEPTORS DYSFUNCTION

1. Presynaptic effect

i) Botulinum toxin: Its an exotoxin that binds to the presynaptic membrane and prevents the release of Ach resulting in weakness and reduction of tone. It is used to control dystonia in which body shows overactive muscular activity.

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Clinical Correlation (fusion-exocytosis complex)

• Tetanus toxin – act on synaptobrevin (CNS) – spastic paralysis

• Botulinum toxins B, D, F and G – act on synaptobrevin (neuromuscular junction) – flaccid paralysis

• Botulinum toxin C – acts on syntaxin – causes flaccid paralysis

• Botulinum toxins A and B – act on SNAP-25 – Causes flaccid paralysis

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• “Botox” (Botulinum toxin)

– local injection of small doses is effective in the treatment of conditions characterized by muscle hyperactivity.

– examples are

• achalasia (lower esophageal sphincter)

• used to remove wrinkles

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82

ii) Lumbert – Eaton syndrome

Antibodies directed against Ca++ channels located in presynaptic terminals and interfere with transmitter release causing weakness.

iii)Neuromyotonia

Patient complains of muscle spasm and stiffness resulting in continuous motor activity in the muscle. It is cased by antibody directed against the presynaptic voltage gated K+ channel so that the nerve terminal is always in a state of depolarization

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83

2. Effects at Postsynaptic level:

i) Curare binds to the acetylcholine receptor (AchR) and prevents Ach from acting on it and so that it induces paralysis.

ii) Myasthenia gravis: is caused by an antibody against the Ach receptors and Ach receptors are reduced hence the Ach released has few Ach receptor available to work and patients complain of weakness that increases with exercise.

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Psychosis

• can be due to hyperactivity

of dopaminergic synapses

• can be treated by

dopamine antagonists

(chlorpromazine and other

antipsychotic drugs), which

inhibit dopamine receptors

in the postsynaptic

membrane.

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85

Synaptic strength

• Can be facilitated like long – term potentiation.

• Can be depressed ( inhibited) by long-term depression.

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86

Classification of Neurotransmitters

• Amines

A. Acetyl choline (Ach)

B. Monoamines

Catecholamines

– Epinephrine

– Nor epinephrine

– Dopamine (Substantia nigra, sympathetic ganglia)

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87

III. Purine derivatives

eg. Adinosine & ATP.

IV. Polypeptides ( a very long list of names)

eg. Enkephaline, hormones ( VIP etc)

( refer to the list in Ganong 21st edition pg.97)

V. Nonsynaptic transmitters

eg. Gases, nitric oxide & cabon mono oxide.

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Excitatory neurotransmitters

• acetylcholine

• norepinephrine

• serotonin

• glutamate

Page 89: Neurotransmitter and Its Synapses -Ppt

Inhibitory neurotransmitters

• GABA

• glycine

• dopamine

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CNS

Skeletal Muscle

Generation of AP in the motorneuron

Depolarization of the terminal buttons

Calcium influx (opening of voltage-gated channel)

Release of neurotransmitters (Ach) in NMJ

Binding of Ach with Ach receptors

Depolarization of motor end plate ( Na+ influx)

Generation of end plate potential (EPP)

Production of action potential

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Generation of AP in the presynaptic neuron

Depolarization of the terminal buttons

Calcium influx (opening of voltage-gated channel)

Release of excitatory neurotransmitters in the synaptic cleft

Binding of excitatory NTA with its receptors

Depolarization of the postsynaptic cell ( Na+ influx)

Generation of excitatory post potential (EPSP)

Production of action potential

EXCITATORY CHEMICAL TRANSMISSION

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Generation of AP in the presynaptic neuron

Depolarization of the terminal buttons

Calcium influx (opening of voltage-gated channel)

Release of inhibitory neurotransmitters in the synaptic cleft

Binding of excitatory NTA with its receptors

Depolarization of the postsynaptic cell ( Cl- influx and K efflux)

Generation of inhibitory post potential (iPSP)

Production of action potential

INHIBITORY CHEMICAL TRANSMISSION


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