Kuliah Neurotransmitter

7/30/2019 Kuliah Neurotransmitter

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FUNCTION OFNEUROTRANSMITTER

SUNARTI

BIOCHEMISTRY DEPARTMENTFACULTY OF MEDICINE

GADJAH MADA UNIVERSITY


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Learning Objective

Students Understand about:1. Definition & Criteria of Neurotransmitter

2. Classification & Neurotransmitter

3. Receptor of Neurotransmitter

4. Neurotransmitter Synthesis


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Neurotransmitters

Neurotransmitter are molecules that act aschemical signals between nerve cells:

to communicate nerve cells with each other & withtarget tissues.

Neurotransmitter are secreted from neurons inresponse to an action potential.

Action potential: - a voltage difference across plasmamembrane, caused by changes in Na+ and K+ gradients,that is propagated along a nerve.

Neurotransmitter diffuse across a synapse toanother excitable cell


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Neurotransmitters

Neurotransmitters criteria1.synthesized in neuron (de novo synthesis)

2.stored in nerve ending prior to release (e.g. insynaptic vesicle)

3.released from pre-synaptic ending in responseto an stimulus.

4.has binding & recognition on postsynaptictarget cell.

5.has mechanism of its inactivation &termination.


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Classification of neurotransmittersbased on chemical composition

Group Example

Amines acetylcholine, norepinephrine,epinephrine, dopamine, serotonin

Aminoacids

glutamate, gamma amino butyric acid(GABA)

Purine ATP, adenosine

Gases nitric oxide

Peptides endorphins, tachykinins


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Neurotransmitter receptors

1. Ionotropic receptors:- are ligand-gated ion channels

mediate inflow of cations (mainly Na+)

- bind transmitter

local depolarization of postsynaptic membrane.


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Neurotransmitter receptors

2. Metabotropic receptors: are coupled to G proteins

influence synthesis of second messengers.

increase cAMP level in postsynaptic cell,

activate Gi proteins reduce cAMP.

Via type Gq proteins, other receptors increaseintracellular Ca2+ concentration.


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Events from neurotransmitter release topostsynaptic excitation or inhibition


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NEUROTRANSMITTER SYNTHESIS

Many neurotransmitters are derived from aminoacids

most of them are synthesized within nervecell.

Neurotransmitter biosynthesis require cofactors

pyridoxal phosphate

thiamine pyrophosphate

vitamin B12

deficiencies of them can lead to neuropathies


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NEUROTRANSMITTER SYNTHESIS

In general, neurotransmitters are formed in the presynaptic terminals of axons

stored in vesicles until released by a transientchange in electrochemical potential along the

axon.

Rapid metabolism of neurotransmitters requiresthe continuous availability of a precursor pool of

amino acids for de novo neurotransmittersynthesis .


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Acetylcholine (Ach)

It is at neuromuscular junctions transmits a signal from a motor nerve to a muscle fiber, result

in contraction of fiber.

Acetylcholine is stored in vesicles of presynaptic membrane

Voltage-gated Ca2 channels of the membrane open whenaction potential reaches membrane influx of Ca2

Ca2 triggers fusion of the vesicles with plasma membrane,

acetylcholine is released into the synaptic cleft.


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Acetylcholine (Ach)

Acetylcholine diffuses acrosssynaptic cleft to bind nicotinicacetylcholine receptors onmuscle cells.

a conformational change

opens narrow portion ofchannel

Na diffuse in & K diffuse out

activates a sequence ofevents

contraction of fiber.


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Acetylcholine (Ach)

Synthesized from dietary choline by adding acetylgroup (via choline acetyltransferase)

Once acetylcholine secretion stops,

the message is rapidly terminated byacetylcholinesterase, an enzyme located on thepostsynaptic membrane.

It is also terminated by diffusion of acetylcholineaway from the synapse.


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Glutamate

Glutamate acts as a

stimulatory transmitter inCNS

More than half of synapses

in brain are glutaminergic.

GABA is most important

inhibitory transmitter in CNS.

Glycine is an inhibitoryneurotransmitter witheffects in spinal cord andin parts of brain.


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In the brain,

ketoglutarate is converted glutamate GABA

Glutamate functions

as an excitatory neurotransmitter within CNS

depolarization of neurons.

Within nerve terminals, glutamate

is generally synthesized de novo from glucose

also can be synthesized from glutamine

Glutamate is stored in vesicles, and its release isCa2 -dependent.


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Catecholamine: Dopamine,Norepinephrine, Epinephrine

Tyrosine hydroxylase

Aromatic amino

acid decarboxylase

(AADC)

Tyrosine L-dopa Dopamine

Dopamine

beta-hydroxylase

epinephrine NorepinephrinePhenylethanolamine

N-methyl transferase

Catecholaminesynthesis


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SYNTHESIS OF CATECHOLAMINE

Tyrosine is

supplied in diet or

synthesized in liver from phenylalanine by phenylalaninehydroxylase

Pathway of catecholamine biosynthesis:

hydroxylation of tyrosine ring by tyrosine hydroxylaseproduce dihydroxyphenylalanine or DOPA.

second step is decarboxylation of DOPA to formdopamine. This reaction requires pyridoxal phosphate.


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Dopamine Dopamin

is a major transmitter in nerves interconnect nuclei of basal ganglia in brain & control

voluntary movement is also found in pathways affecting limbic systems of

brain

involved in emotional responses & memory.

Defects in dopaminergic systems are implicated inschizophrenia

In periphery, dopamine causes vasodilation is used clinically to stimulate renal blood flow is important in treatment of renal failure


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Norepinephrine

also known as noradrenaline

is a major transmitter in sympathetic

nervous system

is transmitter for postganglionic nerves

There are also norepinephrine-containingneurons in CNS, largely in brain stem.


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Epinephrine also known as adrenaline

is produced by adrenal medulla under influenceof Ach-containing nerves analogous to

sympathetic pre ganglionic nerves

is more active than norepinephrine on heart &lungs, causes Redirection of blood from skin to skeletal muscle

Has important stimulatory effects on glycogenmetabolism in liver

is not esential for life but it is possible to removeadrenal medulla without serious consequences.


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Adenoreceptors

are receptor for norepinephrine &epinephrine

are divided into classes

Epinephrine acts on all classes of receptor

Norepinephrine is more specific for alfareceptor.


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Indolamines

Serotonin (5-HT):

is produced in raphe nucleus of brain stem is related to mood, aggression

also has effects on peripheral nervous system &enteric neurons is a powerful vasoconstrictor & increases motility of

gastrointestinal tract

some of serotonin in gut arises not from neurons, butfrom enterochromaffin cells,

similar to chromaffin cells in adrenal medulla thatproduce epinephrine


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Biosynthesis of serotonin

Tryptophan 5-hydroxytryptophan

(5-HTP)

5-hydroxytryptamine

(5-HT)

AADC

Tryptophan hydrolase


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Nitric oxide (NO)

is unconventional neurotransmitter is unstable toxic gases

is produced & released by neurons, but notstored in vesicles

diffuse across cell membranes into extra cellularspace

can be introduced exogenously

is inactivated by conversion to NO2 & CO2


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Nitric oxide (NO) In autonomic & enteric nerves,

NO is produced from arginine by tetrahydrobiopterin-dependent nitric oxide synthase

NO is included in relaxation of both vascular & intestinal

smooth muscle possible regulates mitochondria energy production

In brain, NO may have a role in memory

formation

Excessive NO formation has been implicated inneurodegenerative process associated withParkinsons & Alzhelmers disease


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Peptides

Large molecule that cause change inpostsynaptic cell

Endorphins

Endogenous opiates

Parasympathetic response


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REFERENCES:

Koolman J, and Roehm K-H. 2005. ColorAtlas of Biochemistry. 2ed, revised andenlarged. Thieme Stuttgart . New York

Marks DB, Marks AD and Smith CM. BasicMedical Biochemistry: A Clinical Approach.


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Kuliah Neurotransmitter

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