Regulation of Neurotransmitters in Neuropsychiatric System

7/28/2019 Regulation of Neurotransmitters in Neuropsychiatric System

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Regulation of Neurotransmittersin Neuropsychiatric System

Agnes Kwenang

Department of Biochemistry

Fac. of Medicine UNHAS



IntroductionNerve impulse transmission between cells

is mediated by chemical mechanism, occurs bydifussion of specific chemical compounds, whichact as signals.

Many of amino acids have been studiedintensively because of their function in thenervous system.

As prerequisite knowledge, we shallassume that the student has a degree of familiarity with the basic concepts of

neuroanatomy and neurophysiology.



We shall mainly discuss about theregulation of neurotransmitter inneuropsychiatric system related to metabolism

and function of amino acids group ( glutamate,and GABA) and biogenic amines group whichamino acid act as precursor (catecholaminesand serotonin).



General Learning Objective.

Student should be able to understand theregulation of Neurotransmitters inNeuropsychiatric System.



Specific learning objectives

When student have mastered this topic, studentshould be able to :

1.Define a neurotransmitter.

2.List the neurotransmitters commonly foundin brain and nerve.

3.Describe the metabolism and function of

amino acids act as a neurotransmitter(glutamate, and γ- amino butyric acid = GABA,).



4. Describe the metabolism and function of biogenic amines act as a neurotransmitter(catecholamines, and serotonin).

5. Know the acetylcholine receptor, glutamatereceptor, and dopamine receptor.



1. NEUROTRANSMITTERS definition

Chemical compound is an establishedneurotransmitters must be met five importantcriteria :

1. A synthetic mechanism exists within thepresynaptic neuron;

2. A mechanism of storage (in vesicles) in

evident;



3. The transmitter is released in proportionto the strength of the stimulus (frequentlyof firing).

4. Postsynaptic action of the transmitter hasbeen demonstrated directly bymicroiontophoresis ; and

5. An efficient means for inactivation of thetransmitter is present.



2. Classification of Neurotransmitter

Biochemical Communication Hormones and Neurotransmitters

Table 1. Hormone Origin Major effects

Polypeptidesmet-enkephalinLeu-enkephalinβ -endorphin

Aminoacid derivativesEpinephrine

Norepinephrine

Adenohypophysis

Adrenal medulla

Adrenal medulla

Opioid effects on CNS

- Stimulates contraction of somesmooth muscles and relaxes others.

- Increases heart rate and bloodpressure.

- Stimulates glycogenolysis in liver,muscle

- Stimulates lipolysis in adipose tissue.

- Stimulates arteriole contraction- Decreases peripheral circulation- Stimulates lipolysis in adipose tissue

(Voet: 2 nd Ed. 1263)



Fig. 1



Substances that can be considered possibleNeurotransmitters or Neuromodulators

Biogenic amines• acetyl choline• Catecholamines :

Dopamine*Norepinephrine*Epinephrine*

• 5-hydroxytryptamine= serotonin*

• Other primary aminesHistamineOctopaminePhenylethylaminePhenyletahanolamine

• PolyaminesPutrescineSpermineSpermidine

Amino acidsGlutamic acid*Aspartic acidGlycineΑ-aminobutyric acid*

= GABATaurine

Proline

PurinesAdenosineATP, etc

Table 2.



Neuropeptides

Substance PCarnosineThyrotropin-releasing hormone (TRH)NeurotensinSomatostatinβ -endorphin

EnkephalinAngiotensin IAngiotensin IIOxytocinVasopressinCholecystokininBradykinin

(De Robertis: 690).

AcetylcholineGlutamate

GABAGlycineNorepinephrineDopamineSerotonin

Aspartate

TaurineA large numberof peptides

Regarded asEstablishedtransmitters

Possible candidatetransmitters



Nor epinephrineDopamine

SerotoninVarious neuro

peptides

Sometimes calledNeuromodulators

rather thanNeurotransmitters



- This compound may not initiate a nerveimpulse but may act on adenylate cyclase toincrease or decrease cAMP levels and proteinkinase activity

- They may also diffuse through the extracellularspace to influence a region of the brain greaterthan a single synaptic cleft.

However, the distinction between transmittersand modulators is not exact.



Enzymes in neuromuscular junctions synthesizenot only acetylcholine but also catecholamines,

taurine and GABA.Some synapses in CNS release both Glycine andGABA.

(Metzler 2 nd ed. 1782).



Some of the Neurotransmitters found in

Nervous Tissue.EXCITATORY : Acetylcholine, Aspartate,

Dopamine, Histamine, Norepinephrine, Epinephrine, ATP,glutamate, 5-hydroxytryptamine.

INHIBITORY : GABA, Glycine

(Devlin : p.931)



Fig. 2. Involvement of the astrocytes in the metabolism of GABAand Glutamate







3. Metabolism and function of aminoacids (GABA and Glutamate)

GABA can be made and degraded through aseries of reactions commonly known as theGABA SHUNT. In this reaction, α -KG of the TCAcycle is transaminated to produce glutamate.Gludecarboxylase removes the 1-carboxyl group

to produce GABA. The GABA is catabolized bydeamination and oxidation reactions to producesuccinate that can enter the TCA cycle.



GABA the inhibitory neurotransmitter andglutamate, the excitatory neurotransmitter, mayshare some common routes of metabolisminvolving the astrocytes. Both glutamate andGABA are taken up by astrocytes and convertedto glutamate, which is then transported back

into the presynaptic vesicles.



In the excitatory nerve, glutamine isconverted to glutamate. In the inhibitorynerve, the glutamine is converted to GABAwith glutamate as an intermediate.

(Devlin :937-938)



Fig. 3



Fig. 4



GABA Cycle

In the GABA cycle acetyl and OAA areconverted into Citrate (step a) in theusual way and the citrate is then

converted into 2-oxoglutarate(ketoglutarate). The latter istransformed to L-glutamate either by

direct amination (b) and transamination(c), the amino donor being GABA.



GABA is formed by decarboxylation (d) of glutamate and is catabolized via

transamination (e) to succinic semialdehyde,which is oxidation to succinate and OAA.

The two transamination steps in the pathways

may be linked, as indicated in Fig.3, to form acomplete cycle that paralles the TCA but inwhich 2-oxoglutarate in oxidized to succinate

via glutamate and GABA.No TPP is required, but 2-oxoglutarate, isreductively aminated to glutamate.



The Role of Glutamine in brain.

1. As precursor of Glutamate in neuronal cells.

2. Removed of ammonia to blood.

Brain tissue can form urea, although thisdoes not play a significant role in ammoniaremoval. Formation of Glutamine must bepreceded by synthesis of Glutamate in thebrain itself because the supply of blood

glutamate is adequate to account for theincrease blood glutamine formed in brain inthe presence of high levels of blood

ammonia.











Defective regulation leading to excessively highconcentrations of noradrenaline may be a factor

in the development of schizophrenia.Fate of catecholamines.

After discharge into the synaptic cleft as

transmitters, catecholamines are recovered byan Na +-coupled symporter into the cytosol, fromwhich they can be again concentrated into

vesicles. However, catecholamines in the cytosolare subject to attack by a monoamine oxidasein the outer membrane of mitochondria.



This enzyme is an important protective device;its activity is high enough to remove amines

rapidly.It is a flavoprotein that uses dioxygen and formshydrogen peroxide as a product :

R-CH2-NH3+ + O2 R-CH=O + NH4

+ + H2O2

Amine Aldehyde

A second enzyme in the cytosol methylates the3-hydroxy group in the deaminated catecholcompounds.

MAO



The methylated aldehyde that is formed mayeither be oxidized to an acid or to reduced to an

alcohol. The alcohol (3-methoxy-4-hydroxy-phenylethylene glycol) is the principal product inthe CNS. It is slowly transported into the bloodand excreted in the urine. However, the principalcatechol derivateve in the urine is the acid as itsanion 3-methoxy-4-hydroxy mandelate, formedby the liver from catecholamines released by theadrenal medulla and other tissues.



The determination of its excretion is a usefulguide to the clinical diagnostic management of

tumors such as neuroblastoma andpheochromacytoma that form adrenaline,noradrenaline and dopamine. The compound is

known clinically as vanillmandelate or vanillylmandelate, an example of bastard nomenclatureis excruciating to chemists. Its origin lies in thewidespread occurrence of fragrant methylated3,4-dihydroxy phenyl derivatives in plants;among the is vanillin in vanilla

(Goldstein, 650-651)



Degradation of Dopamine

Fig. 7



Catecholamines are rapidly metabolized by

Catechol-O-methyl transferase = COMT

Monoamine oxidase = MAO

MAO is found in neural tissue and deaminatesserotonin, epinephrine, norepinephrine.

MAO-B is found in extraneural tissues

Nerve impulses regulate catecholaminesynthesis. Nerve stimulation synthesis of catecholamines.



Neuroblastoma- Malignant neoplasma, neural crest and

sympathetic nervous system frequently inadrenal medulla

- 15-50% of neonatal malignancies, 5% of all

childhood cancer death- Some produce : - dopamine

- dopamine and Norepinephrine

- Serum level dopamine hydroxylase correlatewell of urinary vanillyl mandelic acid

- Dopamine excreted as Homovanillic acid



Parkinson’s Disease- 1% of the population over 50 years old

- Clinical manifestation related to deficiencyof Dopamine in areas of the brainresponsible for motor stimulation

- A lack of sufficient dopamine production incertain brain structures like the substancianigra or the destruction of this structure bytoxic compound leads to Parkinson’s Diseaseor Parkinson Syndrome



- The key pathologic characteristic is

degeneration of the pigmented cells in thesubstansia nigra

- Administration of large quantities of L-DOPA

can reverse many of the symptoms in somecases

- Dopamine itself cannot readily enter the

neurons and is rapidly destroyed- Its precursor DOPA, enter the neurons



- Large doses are required because dopadecarboxylase in other tissues will rapidlyconvert it to DOPAMINE unless a

decarboxylase inhibitor is also administrated- Carbidopa is used for this purpose because it

does not enter the neurons

Goldstein, p.652



Fig. 8



Serotonin (5-hydroxy tryptamine)Serotonin is a transmitter in some neurons of the

CNS. These neurons affect many aspects of behavior: appetite, agression, sleep, sexual activity,and so on. The route of formation is like that of noradrenaline.It begin with hydroxylation of C5 in tryptophan bya mixed function oxidase using tetrahydrobiopterinas the electron donor. The 5-hydroxy tryptophan is

decarboxylated to form serotonin bydihydroxyphenylalanine decarboxylase.



The tryptophan-5-monooxygenase is activated.As with the catecholamines, released serotonin isrecovered by an Natrium ion –coupledsymporter. Any of the compound that escapespackaging in vesicles is removed by the action of MAO and aldehyde dehydrogenase, whichconvert it to the corresponding carboxylate for

excretion in the urine.(Goldstein : 654)

N id



Neuropeptides

- Are involved in the mediate of sensory and

emotional responses such as those associatedwith hunger, thirst, sex, pleasure, pain, etc.

- Included in this category are peptides such asenkephalins, endorphins, and substance P.

- Substance P is an excitatory neurotransmitterthat has role in pain transmission, whereas

- endorphins have role in eliminating thesensation of pain

- Some of the peptides found in brain tissues

(Devlin: 937.938 )

5 RECEPTORS



5. RECEPTORS

Fig. 9. Major signaling pathways from metabotropic and

ionotropic receptors in neurons.



Various G proteins control the signaling frommetabotropic receptors using phosphatidylinositol-specific phospholipase C (PI-PLC) andadenylate cyclase or activity directly on K + ionchannels

(Metzler 2 nd p.1775)



Receptor-associated ion channels

Many neurotransmitters, including acetylcholineand glutamate, act to open ion channels thatare part of the receptor protein or of a tight

complete of proteins.- Binding of Acetylcholine to its receptor in the

neuromuscular junction causes the release of Ca2+ ions from the exterior into the musclefiber.



Acetylcholine receptor

• A diagram of the neuromuscular junction• The junction consists of a single nerve terminal separated

from the postsynaptic region by the synaptic cleft.• The motor end-plate is the specialized portion of the muscle

membrane involved in the junction• Junctional folds are prominent; they content a high density of

AChRs in close proximity to the nerve terminal.





• The overall process at the junction: 6 steps• 1. Synthesis of Ach (cytosol nerve terminal)

• Enzyme : Cholineacetyl transferase

• 2.Ach is then incorporated into small membrane-bounddparticles called synaptic vesicles and stored therein.

• 3. Release of Ach from these vesicles into the synaptic cleft isthe next step. This occurs by exocytosis, which involves fusion

of the vesicles with the presynaptic membranes.



• In the resting state , single quanta (= 10.000 molecules of the

transmitter, probably corresponding to the contents of one

synaptic vesicle) are released spontaneously, resulting in smallminiature end-plate potentials(MEPPs).

• When a nerve ending is depolarized by transmission of a nerveimpuls , this process open voltage-sensitive Ca 2+ channels,

permitting an influx of Ca2+ from the synaptic space into thenerve terminal.

• This Ca 2+ plays an essential role in the exocytosis that releaseAch(contents of approximately 200 vspace.esicles) into thesynaptic.



• 4.The released Ach diffuses rapidly across the synaptic cleft toits receptors in the junctional

• When 2 molecules of Ach bind to a receptor, it undergoes aconformatinal change, opening a channel in the receptor that

permits a flux of cations across the membrane.• The consequent entry of Na+ ions results in depolarization of

the muscle mlate potentialembrane, forming the end-platepotential .

• This in turn depolarizes the adjacent muscle membrane, andaction potentials are generated and transmitted along thefiber, resulting in contraction



• 5.When the channel closes, the Ach dissociates and ishydrolyzed by acetylcholinnesterase, which catalyzes thereaction:

• Ach + H 2O Acetate + Choline• This important enzyme is present in high amounts in the basal

lamina of the synaptic space.• 6. The choline recycled into the nerve terminal by an active

transport mechanism, where it can be used again forsynthesis of Ach.



• The Acetylcholine Receptor of the Neuromuscular Junction isa Transmitter-gated ion Channel .

• The channel is closed in the absence of Ach.•

When 2 molecules of the transmitter bind to the receptor,one to each subunit, the protein undergoes aconformational change that results in opening of the ionchannel for approximately 1 ms. During this time, Na+ flows inand K+ flows out. As mentioned above, it is the entry of Na+that results in depolarization of the muscle membrane,generating the end-plate potential.







• Because the presence or absence of Ach itself results inopening and closing of the channel, the Ach receptor isreferred to as a transmitter-gated ion channel

• In contrast to the 2 other types gated channels: voltage-gated

and mechanical gated channels



• Myasthenia Gravis• Autoantibodies damage Acetylcholine receptors and

reduce their numbers.



Binding of glutamate to its ionotropicreceptor in a synaptic ending of dendritecauses an influx of ions into the cytoplasm,initiating an action potential in the dendrite.

In most instances the properties of the receptorchannel favor the rapid flow of Ca 2+ ions intothe cytoplasm.

Many other receptors are 7-helixtransmembrane proteins, which activateguanine nucleotide G proteins.



The G proteins couple some receptors toadenylate cyclase and cyclic AMP-activated

channel, and yet others via Phospholipase C toK+ channels and indirectly to Ca 2+ channels. Allof these G protein coupled receptors are

referred to as metabotropic receptorsA single synapse often contain both ionotropicreceptors and metabotropic receptors.

The ionotropic receptors induce a rapidresponse, while the metabotropic receptors actmore slowly.



However, in most cases the final effect is therelease at Ca 2+ ions into the cytoplasm.

The rapid response may be initiation of anaction potential, while the slow response maybe activation of calmodulin-dependent kinases

and phosphatases(Metzler 2 nd 1774-1775)

Gl



Glutamate receptorsSubdivided into 5 classes :

1. NMDA (N-methyl-D-aspartate)2. AMPA ( α -amino-3hydroxy-5,methyl-4-isoxade propionicacid) = quisqualate receptors

3. Kainate (a compund isolatedfrom seaweed)

4. L-AP4 (a synthetic agonist)

5. Metabotropic receptors

Cationchannels =ionotropicreceptors

Linked to intracellular production of

diacylglycerol and inositol tri-polyphospo



NMDA receptor.

Excitotoxins : kainate, quinolinate

Stimulate NMDA res. causing release of excess glutamate

(depolarization plasma membrane) openion channel. Allow accumulation of Ca 2+ and Na + into the cell → osmotic swelling→ cell death



Fig. 10



It contains 5 distinct sites :

1.A site binds the transmitter glutamate2.A regulatory site that binds glycine

3.A voltage-dependent Mg 2+ binding site

4.A site that binds phencyclidine and PCP5.A site that binds Zn 2+

(Murray : 24 th ,798-799)





• Alzheimer’s disease Is an incurable neuropsychiatric condition in which progressive

impairment of cognitive functions occurs, usuallyaccompanied by affective and behavioral disturbances.

Is the commonest cause of dementiaLost of memory is often the first sign.The basic pathologic picture is of degenerative process

characterized by the loss cells in certain areas of the brain (e.g

the cortex and hippocampus).Amyloid protein is the major constituent of the plaques found

in this disease.





Fig. 11. Schematic diagram illustrating the release of dopamine by a neuron in thesubstantia nigra and also showing the sites of action of drugs that ameliorate orinduce parkinsonism.



The 6 steps described in the text are illustrated butare not numbered in the figure. The sites of actions

of drugs (L-dopa, deprenyl, amantidine, anddopamine receptor agonists (eg. bromocriptine)that are used to treat parkinsonism are also shown;in general these drugs elevate local levels of dopamine. Thus countering its low level inparkinsonism, Sites of actio of certain drugs(reserpine and dopamine receptor antagonists,

such as many neuroleptics) that induceparkinsonism by depleting dopamine or competingwith it are also indicated.

(Murray 24 th ed.805)

D i t t itt



Dopamine acts as a neurotransmitter

As in the case of acetylcholine : divided into 6

steps.= process is involved in the action of monoamines neurotransmitters (norepi-

nephrine, epinephrine).1. Synthesis of dopamine

Reaction is catalyzed by tyrosine

hydroxylase is role-limiting





This produce their effector actions byaffecting adenylyl cyclase positively or

negatively or in at least one case by affectinganother signaling system (Phospholipase Cand Polyphospho inositide cycle).

5. Reuptake of dopamineThis is achieved by a high-affinity transporter(which uses ATP) present in the presynaptic

membrane. The recycled dopa-mine canagain be incorporated into synaptic vesiclesand reused as a transmitter.

d f d



6. Degradation of dopamine can occur

Within the synaptic cleft or following

reuptake, within the presynaptic terminal.Dopamine DOPAC Homovanilic acid.Schizophrenia (homovanil acid in CSF)

Deprenyl acts to inhibit MAO-B.(Murray 24 th ed : 804-805)

MAO-B COMT



• Schizophrenia• Genetic, neurodevelopmental, dopaminergic

factors may be involved in the causation of schizophrenia.

• Genetic linkage studies in schizophrenia sufferfrom a lack of replication.

Dopamine Receptor



Dopamine Receptor

1. Gene cloning, at least five difference (D 1 – D5)

with some subtypes formed by alternativesplicing.

2. They are membrane proteins, at least someof which are mic loops.

3. Most appear to be coupled to G proteins.

4. Some are positively coupled to adenylyl

cyclase (eg. D 1) at least one (D 2) negatively.5. At least one subtype (of D 1) appears to be

coupled to Phospholipase C.

6 S l l d b



6. Some at least, are regulated byphosphorylation.

7. Drug affinities of most neuroleptics for theD2 receptor reflect their potencies intreating Schizophrenia.

8. The various show different anatomicdistributions.

9. The D 4 receptor binds the atyprical

neuroleptic clozapine with an affinity tentimes higher than that of D 2 sites.



10.Five distinct subtypes of the D 4 receptor havebeen recognized, it being the first member of

the catecholamine family of receptors toshow polymorphic variation in the humanpopulation

(Murray 24 th , 811)

Conclusion



Conclusion

We have already discussed :

1.Define a neurotransmitter2.List of the neurotransmitter.

3.The metabolism and function of amino acids actas a neurotransmitter.4.The metabolism and function of biogenicamines act as a neurotransmitter.

5.The receptors of glutamate and dopamine.

References :



De Robertis EDP, De Robertis EMF Jr, 1987. Celland Molecular Biology. 8 th edition,Philadelphia : Lea and Febiger, 690.

Devlin TH, 1993. Textbook of Biochemistry withClinical Correlation 3 rd edition. New York :Wiley-Liss Inc, 931, 937- 938

Goldstein M, 1983. Biochemistry A FunctionalApproach 3 rd edition. Tokyo : WB SaundersCompany,650-652, 654, 648

Koolman J Heinrich Rohm K 2001 Color Atlas



Koolman J, Heinrich –Rohm K, 2001. Color Atlasof Biochemistry. Terjemahan Jakarta :

Penerbit Hipokrates, 316-317Metzler DE, 2003. Biochemistry the Clinical

Reactions of Living Cells. 2 nd edition. Vol 2,

California, Elsevier Science, 958, 959, 1774,1775, 1782

Murray RK, Granner DK, Mayes PA, Rodwell VW,1996. Harper’s Biochemistry. 24 th edition.Stamford : Appleton and Lange, 174, 303,308, 563, 795-796, 798-799, 805.



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Regulation of Neurotransmitters in Neuropsychiatric System