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Neuro biochemistry

Dr. SarYOno, SKp.,MKes.
Medical biochemistry unit

Neuron

Communication by neurons is based on changes
in the membrane’s permeability to ions.
A typical neuron has a dendritic region and an
axonal region.
The dendritic region is specialized to receive
information, typically neurotransmitters; it then
undergoes graded potentials.
The axonal region is specialized to deliver
information: after undergoing action potentials,
neurotransmitters are released from the axon
terminal.

Synapses   An interneuronal junctions Two kinds of synapses Chemical synapses  Electric synapses  .

Chemical Synapses     Vesicles contain neurotransmitters that can alter the ionic conductivity of the postsynaptic membrane The postsynaptic membrane is separated from the presynaptic membrane by a synaptic cleft having a width of 20 nm An increase in sodium ion/Na+. permeability hyperpolarizes the membrane (inhibitory) . permeability tends to depolarize the postsynaptic membrane (excitatory) An increase in potassium ion.

Chemical vs. Electric Synapse Electrical synapse • Impulses can be regenerated without interruption in adjacent cells • Gap junctions – Adjacent cells electrically coupled through a channel – Each gap junction is composed of 12 connexin proteins • Examples – Smooth and cardiac muscles. brain. and glial cells Chemical synapse • Terminal bouton is separated from postsynaptic cell by synaptic cleft • NTs are released from synaptic vesicles • Vesicles fuse with axon membrane and NT released by exocytosis • Amount of NTs released depends upon frequency of AP Examples: otot lurik/rangka .

Electric Synapse Chemical Synapse • Unidirectional • Current Flow Limited By Neurotransmitter Diffusion • Nonlinear Electric Synapse • Bidirectional • Very Fast Current Flow • Linear .Chemical vs.

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Ion gating in axon   Changes in membrane potential caused by ion flow through ion channels Voltage gated (VG) channels open in response to change in membrane potential  Gated channels are part of proteins that comprise the channel  Can be open or closed in response to change  2 types of channels for K+  1 always open  1 closed in resting cell  Channel for Na+  Always closed in resting cells • Some Na+ does leak into the cells .

How A Nerve Cell Fires      Nerve cell membrane is a lipid bilayer with embedded proteins. Neurotransmitter gated channels collapse (‘depolarize’) voltage gradient. Voltage gated channels propagate depolarization in a wave down axon. Channels in membrane can let + ions pass through. . Channels normally closed. ATP-powered ion pumps keep outside of membrane + charged. inside – charged.

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Action potentials   Stimulus causes depolarization to threshold Voltage gated (VG) Na+ channels open  Electrochemical gradient inward     + feedback loop Rapid reversal in membrane potential from –70 to + 30 mV VG Na+ channels become inactivated VG K+ channels open   Electrochemical gradient outward -feedback loop .

do not require active transport  Once AP completed.Action potentials     Depolarization and repolarization occur via diffusion. only open for a fixed period of time Coding for Stimulus Intensity  Increased frequency of AP indicates greater stimulus strength Recruitment  Stronger stimuli can activate more axons with a higher threshold . maximum potential change occurs  Amplitude does not normally become more positive than + 30 mV because VG Na+ channels close quickly and VG K+ channels open  Duration is the same. Na+/K+ ATPase pump extrudes Na+. and recovers K+ All or none  When threshold reached.

(Potensial berjenjang) .

which activates protein kinase Protein kinase phosphorylates synapsins – Synapsins aid in the fusion of synaptic vesicles .Synaptic transmission      NT release is rapid because many vesicles form fusion complexes at docking site AP travels down axon to bouton VG Ca2+ channels open – Ca2+ enters bouton down concentration gradient – Inward diffusion triggers rapid fusion of synaptic vesicles and release of NTs Ca2+ activates calmodulin.

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Inhibit transmiter release Inhibit transmiter uptake .

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organofosfat .

Carroll et al. 2721-36 (1999) . Journal of Medical Chemistry 42.The Dopamine Hypothesis F. I.

Synapses are major targets of
neuroactive drugs
•Caffeine: inhibits adenosine receptors
•Nicotine: activates acetylcholine receptors
•Cocaine: inhibits uptake of DA, NE, 5HT

•Ethanol?

Nicotine
Caffeine

Adenosine

X

X
Cocaine

ACh
Receptor

Synapses are the targets of
therapeutic
drugs
Synapses are also the sites
of actions of many classes of

therapeutic drugs which act upon the brain.

1) Antidepressant drugs generally act by inhibiting the
uptake of serotonin and norepinephrine
2) An important class of analgesic drugs, the opiate
analgesics, activate receptors for neurotransmitters known
as the endorphins and enkephalins
3) Antipsychotic drugs block or inhibit receptors for
dopamine
4) Some types of anticonvulsant drugs potentiate the
effects of the neurotransmitter GABA
•Antidepressant drugs: serotonin uptake inhibitors
• Analgesics (morphine): opiate receptor agonists
• Antipsychotic drugs: DA receptor antagonists
•Anticonvulsant drugs; GABA, modulators
•Antianxiety agents: GABA, modulators

LIFE CYCLE OF A TRANSMITTER

Zigmond et al (1999) Fig 8.3
Stages 1 & 2
Stage 3
Stages 4 & 5
Stage 6 – 9

Accumulation of a precursor amino acid into the neuron which is metabolized to yield the mature
transmitter (ZZ)
Transmitter is then accumulated into vesicles by the vesicular transporter for storage and release.
Transmitter is released into synaptic cleft to interact with post-synaptic receptors or autoreceptors that
regulate transmitter release, synthesis or firing rate.
Inactivation and termination of the action of the released transmitter by reuptake through neuronal
transporter proteins, enzymatic degradation, uptake by glial cells or passive diffusion

serotonin. GABA. glutamat. aspartat Klas IV. histamin Klas III (asam amino). NO . asetilkolin Klas II (amina). norepinefrin.Neurotransmiter (bekerja cepat)     Klas I . epinefrin. dopamin. glisin.

endorfin. substansi P. gastrin. GH. insulin. enkefalin. LH.Neuropeptida (bekerja lambat)     Releasing hormon Peptida hipofise. oksitosin dll Peptida usus dan otak. kalsitonin dll . glukagon dll Dari jaringan lain. prolaktin. bradikinin. angiotensin.

retikulum endoplasma. di sel prasinaps maupun pasca sinaps . aparatus golgi Tempat non sinaps.Neurotransmiter vs neuropeptida     Bekerja cepat Molekul kecil Disintesis di sitosol Tempat kerja di membran pasca sinap Bekerja lambat Molekul besar Disintesis di ribosom.

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otot       rangka dll Norepinefrin. ganglia basalis.di medula spinalis. sebagian korteks Serotonin. serebelum.disekresi di neuron yang badan selnya di batang otak dan hipotalamus Dopamin – di substansia nigra GABA.di rafe medial batang otak Glutamat – di presinap sensorik korteks .Letak neurotransmiter penting Asetilkolin-disekresi di sebagian besar otak.

Ca2+) -Inhibitory transmitter act by opening anion (mainly Cl .Neurotransmitter in the CNS -There is a broad set of different neurotransmitters in the CNS -Neurotransmitters can be activating or inhibitory -Neurotransmitter bind to specific receptors and cause excitatory post synaptic potential (EPSP) or inhibitory post synaptic potentials (IPSP) -Activating transmitter act by opening kation-channels (Na+. inhibitory) -Adrenaline/Noradrenaline (Autonomous nervous system) .K+.-Channels) -Important neurotransmitter: -Acetylcholine (Transmitter of Neuro-muscular junctions) -Dopamine -Serotonin -Glycin (inhibitory) -Aspartate -Glutamate -GABA (-amino-butyric acid.

Neurotransmitters Glutamate Amino Acid Precursors Tyrosine PLP (vit B6) deCO2ase PLP (vit B6) deCO2ase PLP (vit B6) Tryptophan PLP:piridoksal fosfat deCO2ase -Aminobutyrate Dopamine Norepinephrine Epinephrine Serotonin .

O2 Norepinephrine PLP (vit B6) AAA deCO2ase Serotonin (5-HT) . O2 Tyr OHase DOPA PLP (vit B6) AAA deCO2ase Dopamine DOHase Epinephrine Tryptophan THBP: tetrahydrobiopterin THBP.Pathway Catecholamines Tyrosine THBP. O2 Trp OHase PNMT SAHC 5HTP SAM Vit C.

TPP) Acetyl-CoA + choline Choline acetyltransferase Reuptake or diet Acetylcholine Acetylcholinesterase Acetate + choline .Acetylcholine Pyruvate PDH complex (FAD. lipoamide.

norepinephrine.Catecholamine Biosynthesis HO Tyr hydroxylase NH3 + CH2 CHCO 2 - NH3+ O2 HO CH2 CHCO 2- HO Tyrosine HO Catechol HO Dihydroxyphenylalanine (DOPA) DOPA decarboxylase Epinephrine (Adrenaline) CHCH2 NHCH3 OH S-Adenosylhomocysteine Methyl transferase Dopamine hydroxylase DOPA. dopamine. and epinephrine are all neurotransmitters CH2 CH2 NH2 Dopamine SAM HO HO HO HO CO2 CHCH2 NH2 OH Norepinephrine .

L-DOPA in Parkinsonism Blood Brain L-DOPA L-DOPA Dopamine HO CH3 HO Blocks CH2-C-CO2 H Carbidopa NHNH2 Dopamine Parkinsonism associated with dopamine in brain through loss of neurons in basal ganglia. Carbidopa + L-DOPA Blood Brain Barrier .

. also serotonin CHCHO R Aldehyde dehydrogenase HO HO CHCO 2 H Urinary R metabolite R=OH Vanillylmandelic acid (VMA) R=H Homovanillic acid (HVA) .Monoamine Oxidase (MAO) HO MAO (in mitochondria) CHCH2NHR' HO HO HO R R OH OH H R’ H Norepi CH3 Epi H Dopamine MAO inhibitors (e. tranylcypromine) are useful in the treatment of depression Brain levels of dopamine and norepi..g.

Catechol-O-Methyl Transferase (COMT) HO HO COMT CHCH2NHR' Active catecholamine R SAM S-Adenosylhomocysteine • COMT found in cytoplasm HO CHCH2NHR' CH3 O R Inactive metabolite • Terminates activity of catecholamines • Catecholamine excretion products result from combined actions of MAO and COMT • Inhibitors of COMT (e..g. tolcapone) useful in Parkinson’s disease .

Serotonin .Tryptophan Metabolism: Serotonin Formation + NH3 Indole ring + NH3 CH2 CHCO 2 - Trp hydroxylase HO N H Tryptophan (Trp) O2 CH2 CH2 NH2 CH2 CHCO 2 - HO Decarboxylase N H 5-Hydroxytryptophan N H CO2 5-Hydroxytryptamine (5-HT).

vasoconstriction) • Smooth muscle (contraction) • Gastrointestinal tract (enterochromaffin cells .g. regulation of sleep.major storage site) • Drugs affecting serotonin actions used to treat: • Depression •Serotonin-selective reuptake inhibitors (SSRI) • Migraine • Schizophrenia • Obsessive-compulsive disorders • Chemotherapy-induced emesis • Some hallucinogens (e.Serotonin • Serotonin formed in: • Brain (neurotransmitter. mood. appetite) • Platelets (platelet aggregation. LSD) act as serotonin agonists  ..

Serotonin Metabolism: 5-HIAA CH2 CH2NH2 HO MAO CH2CHO HO N H N H Serotonin Dehydrogenase CH2 CO 2H HO Carcinoid tumors: • Malignant GI tumor type • Excretion of large amounts of 5-HIAA N H 5-Hydroxyindole acetic acid (5-HIAA) (Urine) .

Serotonin Metabolism: Melatonin CH2 CH2 NH2 HO 2 Steps N H Serotonin CH2CH2 NHCOCH 3 H3CO N H Melatonin Melatonin: • Formed principally in pineal gland • Synthesis controlled by light. among other factors • Induces skin lightening • Suppresses ovarian function • Possible use in sleep disorders .

Nitric Oxide • Cell messenger • Implicated in a wide range of physiological and pathophysiological events: • Vasodilation: • Activates guanylyl cyclase cGMP Glycerin + NO • Nitroglycerin • Sildenafil (Viagra): in vascular smooth muscle: Blocks NO cGMP Phosphodiesterase-5 GMP .

Synthesis of Nitric Oxide NH2 NH3 + Arginine + H2 N=C-HNCH 2 CH 2 CH 2 CHCO 2 Nitric oxide synthase (NOS) NH3 + NH2 CONH CH 2 CH 2 CH 2 CHCO 2 - Citrulline + NO .

Tryptophan Metabolism: Biosynthesis of Nicotinic Acid + NH3 CH2 CHCO 2 - CO 2H Several steps N H Tryptophan N Nicotinic acid (Niacin) Nicotinamide adenine dinucleotide (NAD) .

GABA  GLUTAMATE  GABA + CO2 GLU DECARBOXYLASE GABA IS THE MAJOR INHIBITORY NEURO-TRANSMITTER IN BRAIN  GLU IS THE MAJOR EXCITATORY NEURO-TRANSMITTER STIMULATION OF NEURONS BY GABA    PERMEABILITY TO CHLORIDE IONS      BENZODIAZEPINES (VALIUM) ENHANCE MEMBRANE PERMEABILITY OF Cl IONS BY GABA GABAPENTIN PROTECTS AGAINST GLU EXCITOTOXICITY .

HISTAMINE  HISTIDINE  HISTAMINE + CO2   HIS DECARBOXYLASE HISTAMINES INVOLVED IN  ALLERGIC RESPONSE  H1 RECEPTORS IN GUT. ETC . BRONCHI • STIMULATION  SMOOTH MUSCLE CONTRN’ • H1 RECEPTOR ANTAGONISTS – CLARITIN. ZYRTEC.

HISTAMINE  HISTAMINES INVOLVED IN   CONTROL OF ACID SECRETION IN STOMACH  H RECEPTORS 2 • STIMULATION   HCl SECRETION • H2 ANTAGONISTS – CIMETIDINE – RANITIDINE H2 RECEPTORS IN HEART  STIMULATION   HEART RATE .

6.SEROTONIN  TRP  5-HYDROXYTRYPTOPHAN    5-HT  SEROTONIN + CO2   TRP HYDROXYLASE REQUIRES 5.7.8 TETRAHYDROBIOPTERIN AROMATIC ACID DECARBOXYLASE SEROTONIN CAUSES    SMOOTH MUSCLE CONTRACTION BRAIN NEUROTRANSMITTER MELATONIN SYNTHESIZED IN PINEAL GLAND .

DOPAMINE  AMINE DERIVATIVES OF CATECHOL  REACTIONS:  TYR  L-DOPA   L-DOPA  DOPAMINE + CO2   AROMATIC ACID DECARBOXYLASE DOPAMINE  NOREPINEPHRINE   TYR HYDROXYLASE DOPAMINE β-HYDROXYLASE NOREPINEPHRINE  EPINEPHRINE  REQUIRES SAM . NOREPINEPHRINE.CATECHOLAMINES  EPI.

CATECHOLAMINE PRODUCTION STOPS AT DOPAMINE      PARKINSON’S DISEASE: DEGENERATION OF SUBSTANTIA NIGRA   DOPAMINE TREAT BY GIVING PRECURSOR.L-DOPA AND DOPAMINE  IN SUBSTANTIA NIGRA. MEDULLA CELLS TO BRAIN L-DOPA A PRECURSOR OF MELANIN PRODUCTION . L-DOPA DOPAMINE CANNOT CROSS BLOOD/BRAIN BARRIER TRANSPLANTATION OF ADR.

NOREPINEPHRINE  EPINEPHRINE .

S-ADENOSYLMETHIONINE .

ACTIONS OF NOREPINEPHRINE  NOT NEARLY AS ACTIVE AS EPINEPHRINE   CIRCULATORY SYSTEM     DURING EXTREME STRESS CONSTRICTS GREAT VEINS (2) VASOCONSTRICTIVE TO SKIN (1) VASOCONSTRICTION (1) EFFECTS ON  GI TRACT  SPLEEN  PANCREAS  KIDNEYS NEUROTRANSMITTER IN THE BRAIN .

ACTIONS OF EPINEPHRINE  AS AN INSULIN ANTAGONIST  ACTIVATES MUSCLE GLYCOGEN PHOSPHORYLASE   TRIGGERS PHOSPHORYLATION (ACTIVATION) OF HORMONE-SENSITIVE LIPASE IN FAT CELLS     GLUCOSE-6-P USED IN GLYCOLYSIS MOBILIZES FAT BY HYDROLYZING TGs GLYCOGEN BREAKDOWN IN LIVER ACTIVATES GLUCONEOGENESIS IN LIVER INHIBITS FATTY ACID SYNTHESIS .

ACTIONS OF EPINEPHRINE  ON CARDIAC MUSCLE  β1 -ADRENERGIC RECEPTOR STIMULATION   HEART RATE AND CARDIAC OUTPUT • β-BLOCKERS   BLOOD PRESSURE   DILATES CORONARY ARTERIES (β2) ON SMOOTH MUSCLE (β2-ADRENERGIC)   IN BRONCHIOLES. ETC  ASTHMA MEDICATIONS . FOR EXAMPLE  MUSCLE RELAXATION  ACTIVATION OF G-PROTEINS • cAMP .

Phenylalanine and tyrosine are precursors of the catecholamines. norepinephrine. • Dopamine has a role in the pathogenic mechanisms that cause Parkinson’s disease. dopamine. . • Parkinson’s disease is characterized by a loss of dopaminergic neurons that results in diminished levels of dopamine in the striatum. and epinephrine.

.Dopamine is synthesized in the cytoplasm and (normally) immediately sequestered in intracellular storage vesicles through the agency of α-synuclein.

2. Biosynthesis of the catecholamines phenylalanine tyrosine Tyrosine 3-monooxygenase* dihydroxyphenylalanine (DOPA) dopamine norepinephrine epinephrine *Rate-determining step .

One recent postmortem study examined the capacity to synthesize 5-hydroxytryptamine and the capacity to bind 5hydroxytryptamine.Tryptophan precursor of 5-hydroxy-tryptamine (serotonin). Their findings indicated that the brains of suicide victims had had reduced serotonergic function. . •    The broad actions of the neurotransmitter 5hydroxytryptamine involve effects upon emotion. suicide and depression have been associated with reduced serotonergic transmission. mood. and reward.

.2. Biosynthesis of 5-hydroxytryptamine In the conversion of tryptophan into 5-hydroxytryptamine. tryptophan undergoes hydroxylation to yield 5-hydroxytryptophan that is then decarboxylated to yield 5-hydroxytryptamine.

.Reactions that convert tyrosine or tryptophan into neurotransmitters.

It has been shown that that the intensity and duration of catecholamine signaling at the synapse is governed by the efficiency of the re-uptake of released neurotransmitter. The finding that a dopamine “re-uptake” transporter can serve as a cocaine “receptor” has provided new insight into mechanisms of addiction. Re-uptake occurs by means of highaffinity membrane transporters. .

.Cartoon depicting the binding of cocaine (and other agents) by the membrane transporters that facilitate reuptake.

In this way it contributes to the anti-thrombogenic properties of the endothelium. This a second messenger that appears to have distinctly different functions in different cell types. Arginine is the precursor of the second messenger nitric oxide. For example. the nitric oxide synthesized by platelets is seen to inhibit platelet aggregation and adherence.D. .

a diminution in nitric oxide was associated with glucocorticoid-induced hypertension. .In the kidney (in experimental animals). Such studies were carried out because it had been suggested that decreased nitric oxide contributes to the impaired endothelium-dependent vasodilatation seen in essential hypertension.

Hence. cortical cells from patients with Alzheimer’s disease showed increased levels of nitric oxide mRNA and protein.On the other hand. nitric oxide is generally considered to be a vasodilator. From an overview however. nitric oxide has been associated with the progression of Alzheimer’s disease. .

As a second messenger. .e. The cyclic GMP then up regulates a cyclic GMP-dependent protein kinase. in turn. phosphorylates specific substrates in order to bring about its effects. i. nitric oxide up regulates the activity of the enzyme that synthesizes cyclic GMP.. guanylyl cyclase. The protein kinase.

2. They each catalyze the complex oxidation/reduction reaction that utilizes one of arginine’s nitrogen atoms in order to make the “free radical” nitric oxide. . Biosynthesis of nitric oxide Nitric oxide is synthesized by the enzyme nitric oxide synthase (NOS). and the inducible nitric oxide synthase (iNOS). There are three types of enzymes. the endothelial nitric oxide synthase (eNOS). the neuronal nitric oxide synthase (nNOS).

and FMN along with tetrahydrobiopterin (BH4) and heme (Fe). . FAD.The NOS reaction requires NADPH.

.An electron transport chain has been formulated for the reaction.

V. . Glutamate and its Receptors and Signaling The amino acid glutamate is an endogenous excitatory neurotransmitter. utilized by neurons in the human central nervous system and the peripheral nervous system. Glutamate acts by binding glutamate receptors that allow it to play a pivotal role in synaptic mechanisms involved in learning and memory.

or efficiency. of synaptic transmission varies in an activity-dependent manner. the phenomenon in which the efficacy. The effect can be transient (short-term) or persistent (long-term).Learning and memory involve synaptic plasticity. Signal transduction involving glutamate receptors governs the reactions involved in these processes.. .

Cartoon depicting signal transduction involving the glutamate receptor in the phenomenon of synaptic plasticity. .

the NMDA (N-methyl-D-aspartate). There are three of the former.Glutamate binds two types of receptors. and the kainate receptors. They are referred to as ionotropic because they associate to form cation channels that facilitate the entry of Ca2+ (or Na+) into the cell. the ionotropic glutamate receptors and the metabotropic receptors. the AMPA (α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid). .

Glutamate receptor molecules form dimers and then tetramers that function as ion channels. .

the protein generally undergoes a conformational change that can alter its properties and its activity. They are locked in a “closed” configuration when an antagonist is bound.These ion channels are ligand-gated channels that assume an “open” configuration upon glutamate (or agonist) binding. . It should be remembered that when a protein binds a ligand.

Effect of an antagonist. a partial agonist. and the full agonist. glutamate upon the conformation of the glutamate receptor. .

Excessively activated receptors lead to brain damage seen with cerebral ischemia. and the neurodegeneration associated with Huntington’s chorea. epileptic disorders. however. traumatic brain injury. and Alzheimer’s disease.Excessive glutamate binding to glutamate receptors in the brain can bring about excitotoxic neuronal cell death. .

These excitotoxic effects are due. to signaling downstream of certain glutamate receptors that leads to in increased intracellular Ca2+. in part. The ionotropic N-methyl-D-aspartate (NMDA) glutamate receptor is one of the principal ones that facilitates the entry of extracellular calcium (Ca2+) into the neuronal cell. .

among other actions. up regulate the synthesis of nitric oxide by the nNOS. .Calcium (Ca2+) that enters the neuronal cell by way of NMDA channels can.

As a result of increasing intracellular Ca2+ NMDA glutamate receptors have broad influence. . modulating the activities of a variety of protein kinases and phosphoprotein phosphatases.

. it has been suggested that the NMDA glutamate receptor and a (D1) dopamine receptor cooperate in the molecular mechanisms of compulsion and persistence as related to drug adiction.Recently.