NEUROBIOCHEMISTRY

Departemen Biokimia
Fakultas Kedikteran Unsoed
Basic unit = neuron

 Dendrites to be designed to receive

electrical information from other
cells.
 Soma/cell body processes electrical
information
 Axon sends electrical information
down neuron
 End of axon is terminal, which can
translate electrical message into
chemical message
Neurons do not physically connect

biochemical connections and

communication occurs in
space between neurons: the
synapse
Synapses: a junction that
mediates information transfer
Each synapse consists of two
neurons, separated by a tiny
gap (so tiny, it is measured
in nanometers).
Neurons can
synapse with:

1. Neurons

2. Muscle

3. Glands
Supporting the neurons are glial cells of different
types and functions
5 type of glial cells :
• schwan cell,
• oligodendrosit,
• mikroglia,
• ependimal cell
• Astrosit
The number of glial cell 10x
greater than neuron
• Menempati ruangan antar neuron
• provide physical and metabolic
support
• Assist in the clearance of overspilled
neurotransmitter
• Help organize the differentiation of
the brain
• Directly augment the function of
neurons, as in the case of the Schwann
cell
• Not electrically active
Myelin in the Peripheral and Central Nervous Systems

In multiple sclerosis (MS), patches of myelin

are destroyed in the brain and spinal cord
 The brain,the most complex organ is characterized by a
remarkable level of interaction between neurons

 The neuron is the functional unit

 Neuron are so highly differentiated,
 Neuron have little capacity for
regeneration
 Kandungan lipid tinggi (50%)
The brain that serves as a center nervous system has virtually no
reserves of chemical energy

 this organ is 2% of total adult weight

 for 20% of overall oxygen consumption (pada kondisi istirahat)
 does not utilize fatty acids for energy production. Under certain
conditions it may utilize β-hydroxybutyrate or lactate derived from
circulation.
 Large amount of energy is required to maintain the distribution
gradients of cations across cellular membranes
Energi untuk otak

 Pada kondisi normal?

 Pada kondisi kelaparan berkepanjangan?

 Adakah Cadangan glikogen di dalam sel saraf otak ?

 Bagaimana dengan Asam lemak ?
 Bagaimana dengan asam amino? Kemampuan glukoneogenesis?
Summary of Metabolism
DIET

Fats Carbohydrates Proteins

Free fatty acids + glycerol

Protein
Glycogenesis Amino synthesis
Glucose acids
Fat Lipogenesis
Lipogenesis

stores Excess glucose

Glycogen Body
stores protein
Lipolysis Urine
Glycogenolysis
Glucose pool
Gluconeogenesis
Free fatty
Range of normal
acid pool Amino acid
plasma glucose
pool

Metabolism in
most tissues Brain
Excess nutrients metabolism

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-2
Neurons are highly polarized cells that propagate nerve impulse / action
potentials from the axon hillock to the axon terminal

 When new information is received by the first neuron, it creates an electrical impulse
 Electrical impuls can travel through the body without a significant loss of impulse strength.
Such unique features are based on semi-permeable excitable membranes that
alter permeation to small chemical molecules and to cations.
 Neurons
When the action potential reaches the axon
terminals it sends a signal to the next cell via a
synapse (see later) or similar structure.

This will result in…

Muscle contraction

Hormone release

Change in activity of an organ e.g. heart

A signal being generated in the next neuron in the pathway

 When electrical impulse travels down axon terminal, a
chemical is released, a neurotransmitter

 neurotransmitters are stored in small, bubble-like

compartments called vesicles
 Each vesicle tends to hold a single kind of
neurotransmitter
 The vesicles travel like tiny ferryboats to the end
of the neuron, where they dock, waiting to be
released
 When nerve terminal is activated, it will open
voltage-gated ion channel
 rise in Ca 2+ triggers fusion of synaptic vesicles
with the membrane of the neuron &
neurotransmitter are released into synaptic cleft
via exocytosis
 Neurotransmitter, released by terminal depolarization,
diffuse across the synapse and activates postsynaptic
receptors

 There may be several different

receptors on the postsynaptic
membrane
 Neurotransmitter only "fits" in one
receptor, binds to specific receptors
in target neuron, like “lock and key”
 postsynaptic receptor activation
changes ion permeability (ligand-
gated ion channels)
An important feature of synaptic transmission is the active termination of
neurotransmitter effects

This occurs in two ways :

the clearance of neurotransmitter
the modification of receptors.
 In general, neurotransmitters are
cleared by:
 active uptake back into the
presynaptic nerve terminal
membrane
 quickly destroyed by enzyme
 Other uptake system exist in the
glial cells (astrocytes)
 So, after neurotransmitter release, the
neuron recycles the empty vesicles,
refilling and reusing them several more
times before they need to be replaced.
An important recent concept is that of autoinhibition.

 As well as being present on the surface of postsynaptic

neurons, neurotransmitter receptors are found on presynaptic
neurons.
 Many presynaptic neuron contain receptors for their own
neurotransmitter, for example :adrenoceptors in the case of
noradrenaline (norepinephrine).
 In general, presynaptic neuron receptors act to inhibit further
release of neurotransmitter, so can be considered a form of
negative feedback that limit overactivation.
When even one part of the process breaks down,
if a molecule fails to do its job properly
if the vesicles release their neurotransmitters at the wrong speed
— serious problems may develop.
Many brain disorders and nervous system diseases : autism, schizophrenia,
Alzheimer’s disease, epilepsy, and even botulinum poisoning  problems at
the synapse.

 —Scientists have discovered, for example, that botulinum, bacterial toxins

that cause the often-fatal form of food poisoning known as botulism,
attack proteins important in neurotransmitter release.
 Botulinum cuts these proteins in two and prevents them from helping
vesicles release their neurotransmitters, leading to paralysis.
 However, physicians now use botulinum to intentionally paralyze muscles to
alleviate painful muscle spasms caused by the neurological disorder
dystonia.
 Neurotransmitters found in the nervous system

 50 different neurotransmitters have been identified

 Classified chemically and functionally
 Chemically:
ACh, Biogenic amines, Peptides
 Functionally:
Excitatory or inhibitory
Small molecule neurotransmitter : Ach, GABA,amino
acid neurotransmitter
Peptide neurotransmitter : hormonal activity
Direct/Ionotropic (open ion channels) or
Indirect/metabotropic (activate G-proteins) that
create a metabolic change in cell
 exitatory inhibitory
Acetylcholine GABA
Aspartate Glycine
Dopamine
Histamine
Norepinephrine
Epinephrine
Glutamate
Serotoni
 Acetylcholine : First neurotransmitter identified,
and best understood

 major transmitter used at

neuromuscular junctions
(NMJs)
 enclosed in synaptic vesicles
 Degraded by the enzyme
acetylcholinesterase (AChE)
 acetylcholine

 Released by:
 All neurons that stimulate
skeletal muscle
 Some neurons in the
autonomic nervous
system
 Binds to cholinergic
receptors :
 nicotinic or muscarinic
receptors
Acetylcholine is synthesized from acetyl CoA and choline

 As soon as acetylcholine is
synthesized, it is stored within
synaptic vesicles
 hydrolyzed in the synaptic cleft by
acetylcholinesterase (choline is
reused by Na+/ choline symporter)
Signaling at the Neuromuscular Junction (NMJ)

 type of nerve transmission occurs when

an axon terminates on a skeletal muscle
fiber
 skeletal muscle membrane is thickened
and is referred to as the motor end plate.
 The space between the terminal
boutons and the motor end plate is
similar to the synaptic cleft that exists
where the pre- and post-synaptic
membranes of neurons
 neuromuscular nerve transmission

 Action potential change in membrane

permeability allows Ca2+
 Exocytosis of Ach-containing vesicle
 Ach binds to nicotinic receptors in motor end
plate membrane.
 Activation of nicotinic receptors results in
increase Na+
 Influx Na+ into skeletal muscle cell produces
depolarizing potential and muscle contraction is
initiated.
devastating disease that results from defects in the
neuromuscular nerve transmission is myasthenia gravis
(MG)

 Characteristic features : weakened skeletal muscles that tire with very little
exertion.
 MG is an auto-immune disease associated with antibodies to muscle type
nicotinic receptors. Binding of the antibodies to the receptor results in
receptor destruction
 In most patients : there is a 70%–90% reduction in motor end plate nicotinic
receptor number.
 Treatment : acetylcholinesterase inhibitors. The use of these types of drugs
allows for enhanced levels of ACh at the motor end plate during repeated
muscle stimulation.
 Amino acid neurotransmitters

 Glutamate and glycine

•Present in all cells - Differences
among neurons are quantitative NOT
qualitative
•Vesicular transporters are specific to
these neurons
 Glutamic acid decarboxylase (GAD)
•Key enzyme in GABA synthesis
•Good marker for GABAergic neurons
•One chemical step difference
between major excitatory transmitter
and major inhibitory transmitter
 Glutamate acts as the major excitatory transmitter in the
brain

 Postsynaptic glutamatergic neurons

possess three types of receptors that
bind glutamate released from
presynaptic neurons.
 Brain glutamate-glutamine cycle
 Ammonium ion (NH4+) in the blood is
taken up by astrocytes and
incorporated into glutamate via
glutamine synthetase.
 The glutamine then is transported to
presynaptic neurons
 Within the presynaptic neuron
glutamate is formed from the
glutamine via the action of
glutaminase
 The glutamate is packaged in
secretory vesicles for release
following activation of an action
potential
 Glutamate in the synaptic cleft can
be taken up by astrocytes
 Within the astrocyte the glutamate is
converted back to glutamine.
 Some of the astrocyte glutamine
can be transported into the blood
 GABA (γ-aminobutyrate ): Main inhibitory
neurotransmitter in the brain
 GABA is synthesized from glutamate
 is a major inhibitor of presynaptic
transmission in the CNS, and also in
the retina
 Neurons that secrete GABA are
termed GABAergic
 GABA cannot cross the blood-brain-
barrier and as such must be
synthesized within neurons in the CNS
 The synthesis of GABA in the brain
occurs via a metabolic pathway
referred to as the GABA shunt.
 Glucose is the principal precursor
for GABA production via its
conversion to α-ketoglutarate in the
TCA cycle.
 GABA exerts its effects by binding to
two distinct receptors, GABA-A
(GABAA) and GABA-B (GABAB).
 GABA has been implicated in
several neurological and
psychiatric disorders of
humans :
 Huntington’s,
 chorea,
 epilepsy,
 alcoholism,
 Parkinson’s disease
 and anxiety disorders
Neurotransmitters Biogenic Amines : Catecholamines –
dopamine, norepinephrine (NE), and epinephrine (EP)

 Synthesized from AA tyrosine

 Norepinephrine and dopamine
are synthesized in axonal
terminals
 Epinephrine is released by the
adrenal medulla as a hormone
 Catecholaminergic Neurons
Involved in : movement, mood,
attention, and visceral function
 Dopamine is neurotransmitter in the brain that
plays vital roles in a variety of different behaviors

 Dopamine release enhanced by amfetamines

 Reuptake block by cocaine
 The major behaviors dopamine affects are
movement, cognition, pleasure, and motivation
 abnormalities in brain dopamine are associated with
many neurological and psychiatric disorders
including Parkinson's disease, schizophrenia
 Dopamine is not easily transported into the brain
whereas its immediate, Dopa (L-3,4-
dihydroxyphenylalanine), is readily taken in
 Hence, a marked improvement has been achieved in
Parkinson’s treatment with L-Dopa
 Norepinephrine ( 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
– “Feeling good” NT
– Release enhanced by
amphetamines
– Removal from synapse blocked by
antidepressants and cocaine
 Serotonin (5-HT,5 hydroxytryptamine) is derived from
tryptophan

 Regulates mood, emotional

behavior, sleep
 Synthesis of serotonin
•Limited by the availability of
blood tryptophan (diet)
 Drugs that block its uptake
relieve anxiety and depression
SSRI’s = selective serotonin
reuptake inhibitors
Include drugs such as
Prozac,
Celexa, Lexapro, Zoloft
REFERENCE

 Harper's Illustrated Biochemistry( 26th Ed, 2003)

 Marks' Basic Medical Biochemistry - A Clinical Approach (2nd Edition)
 Baijaieh , S,M., Scheller, R.H., 1996. The biochemistry of Neurotransmitter
Secretion. The journal of Biological Chemistry. 270( 5 ): 1971-4