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Neurotransmitters &

By: June Luhulima, dr., MS, SpKl


Neuromodulators!
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Pendahuluan

• Telah dijelaskan peran neurotransmitters dalam


memicu EPSPs dan IPSPs.

• Messengers kimia tertentu memicu respon yang


komplex yang tidak bisa disebut EPSPs atau IPSPs.

• “Modulasi” digunakan untuk respon yang kompleks


dan messengers yang menyebabkannya disebut
neuromodulators.

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Neuromodulators tertentu sering disintesis oleh
sel presinatik, dan dibebaskan bersama dengan
neurotransmiter

• Gambaran komplesitas bisa dilihat bahwa hormon


tertentu, agen parakrin dan “messengers” yang
digunakan oleh sistem imun, bertindak sebagai
neuromodulators.

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• Neuromodulators sering memodifikasi respon sel
sinaptik terhadap neurotransmitters tertentu,
memperkuat atau meredam efektifitas kegiatan
sinaptik yang sedang berlangsung

• Atau, mereka bisa mengubah sintesis sel


presinaptik, pembebasan, “re-uptake” atau
metabolisme transmiter.

• Dengan kata lain, mereka mengubah efektifitas


sinaps

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• Secara umum, reseptor neurotransmitters
mempengaruhi saluran ion secara langsung yaitu
eksitasi atau inhibisi sel postsinaps.

• Mekanisme ini terjadi dalam milli detik.

• Reseptors untuk neuromodulators, lebih sering


mengubah proses metabolik di dalam saraf,
umumnya melalui G proteins yang bergabung
dengan sistem “second-messenger”.

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Perubahan tersebut dapat terjadi dalam menit, jam
atau bahkan beberapa hari termasuk perubahan
aktifitas enzim atau dengan mempengaruhi
transkripsi DNA, dalam sintesis protein.

• Jadi, neurotransmitter terlibat dalam komunikasi


yang cepat, sedangkan neuromodulator cenderung
berhubungan dengan peristiwa yang lambat seperti
“belajar”, (develop) “berkembang”, suasana
motivasi atau beberapa kegiatan sensoris atau
motoris.

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Acetylcholine

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• Acetylcholine adalah neurotransmitter utama di
dalam S.S. Perifer, dan juga ada di dalam otak.
Serat yang membebaskan ACh disebut serat
cholinergic (kolinergik).
• Badan sel saraf kolinergik di otak terkonsentrasi di
sebagian kecil area, tetapi akson terdistribusi
secara luas.

• Beberapa reseptor ACh berespon tidak hanya


terhadap asetilkolin, tetapi juga terhadap obat
nikotin, dan oleh karena itu dikenal sebagai
reseptor nicotinic.

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Kejadian
biokimia di ujung
saraf kolinergik

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• Reseptor Nicotinic di otak penting dalam fungsi
kognitif.
• Misalnya, satu sistem kolinergik yang
menggunakan reseptor nicotinic memainkan
peran utama dalam “perhatian”, “belajar”, dan
“memori” dengan memperkuat kemampuan untuk
mendeteksi dan berespon terhadap rangsang
yang berarti

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Model of the nicotinic acetylcholine-gated ion
channel, 3 dimensi

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• Neurons associated with this system Ach
degenerate in people with Alzheimer’s disease, a
brain disease that is usually age-related and is the
most common cause of declining intellectual
function in late life, affecting 10 to 15 % of people
age > 65, and 50 % > age 85.

• Because of the degeneration of cholinergic


neurons, this disease is associated with a
decreased amount of ACh in certain areas of the
brain and even the loss of the postsynaptic neurons
that would have responded to it.

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• These defects and those in other neurotransmitter
systems that are affected in this disease are related
to the declining language and perceptual abilities,
confusion, and memory loss that characterize
Alzheimer’s victims.

• The exact causes of this degeneration are unknown

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Biogenic Amines

• The biogenic amines are neurotransmitters that are


synthesized from amino acids and contain an amino
group (R–NH2).

• The most common biogenic amines are dopamine,


norepinephrine, serotonin, and histamine

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Peristiwa biokimia
pada ujung saraf
noradrenergik

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Catecholamines
• Synthesis and release of the catecholamines from
the presynaptic terminals are strongly modulated
by autoreceptors on the presynaptic terminals.

• After activation of the receptors on the


postsynaptic cell, the catecholamine concentration
in the synaptic cleft declines, mainly because the
catecholamine is actively transported back into the
axon terminal.

• The catecholamine neurotransmitters are also


broken down in both the extracellular fluid and the
axon terminal by enzymes such as monoamine
oxidase.

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• Monoamine oxidase inhibitors, which increase the
brain extracellular concentration of the
catecholamine neurotransmitters, are used in the
treatment of diseases such as depression, as will
be discussed in

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Dopamine

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Norepinephrine

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• The catecholamines exert a much greater influence
in the central nervous system than the number of
neurons alone, would suggest, possibly because of
their neuromodulator-like effects on postsynaptic
neurons.

• These neurotransmitters play essential roles in


states of consciousness, mood, motivation, directed
attention, movement, blood-pressure regulation, and
hormone release, all functions that will be covered
in later chapters.

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• There are two major classes of receptors for
norepinephrine and epinephrine:

• alpha-adrenergic receptors and beta-


adrenergic receptors (these are also called
alpha-adrenoceptors and beta-
adrenoceptors).

• The major way of distinguishing between the two


classes of receptors is that they are influenced by
different drugs. Both alpha- and beta-adrenergic
receptors can be subdivided still further (alpha1
and alpha2
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Serotonin

• Serotonin, while not a catecholamine, serotonin (5-


hydroxytryptamine, or 5-HT) is an important
biogenic amine. It is produced from tryptophan, an
essential amino acid.

• Its effects generally have a slow onset, indicating


that it works as a neuromodulator. Serotonin
releasing neurons innervate virtually every
structure in the brain and spinal cord and operate
via at least 16 different receptor types.

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• In general, serotonin has an excitatory effect on
pathways that are involved in the control of muscles,
and an inhibitory effect on pathways that mediate
sensations.

• The activity of serotonergic neurons is lowest or


absent during sleep and highest during states of
alert wakefulness. In addition to their contributions
to motor activity and sleep, serotonergic pathways
also function in the regulation of food intake,
reproductive behavior, and emotional states such as
mood and anxiety

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• Serotonin is also present in many non-neural cells
(for example, blood platelets and certain cells of the
immune system and digestive tract).

• In fact, the brain contains only 1 to 2 percent of the


body’s serotonin

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Amino Acid Neurotransmitters

• Two so-called excitatory amino acids, glutamate and


aspartate, serve as neurotransmitters at the vast
majority of excitatory synapses in the central
nervous system.

• In fact, most excitatory synapses in the brain release


glutamate. The excitatory amino acids function in
learning, memory, and neural development.

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Amino Acid Neurotransmitters

They are also implicated in


• epilepsy,
• Alzheimer’s and
• Parkinson’s diseases, and
• the neural damage that follows strokes, brain
trauma, and other conditions of low oxygen
availability.
• drugs, such as phencyclidine (“angel dust”).

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GABA

• GABA (gamma-aminobutyric acid) and the amino


acid glycine are the major inhibitory
neurotransmitters in the central nervous system.
(GABA is not one of the 20 amino acids used to build
proteins, but because it is a modified form of
glutamate, it is classified with the amino acid
neurotransmitters.)

• Drugs such as Valium that reduce anxiety, guard


against seizures, and induce sleep enhance the
action of GABA.

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Neuropeptides

The neuropeptides are composed of two or more


amino acids linked together by peptide bonds.
• Some 85 neuropeptides have been found, but
their physiological roles are often unknown. It
seems that evolution has selected the same
chemical messengers for use in widely differing
circumstances,
• and many of the neuropeptides had been
previously identified in nonneural tissue where
they function as hormones or paracrine agents.

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• The neuropeptides are formed differently from other
neurotransmitters, which are synthesized in the
axon terminals by very few enzyme-mediated steps.
• The neuropeptides, in contrast, are derived from
large precursor proteins, which in themselves have
little, if any, inherent biological activity.
• The synthesis of these precursors is directed by
mRNA and occurs on ribosomes, which exist only in
the cell body and large dendrites of the neuron,
often a considerable distance from axon terminals
or varicosities where the peptides are released

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• In the cell body, the precursor protein is packaged
into vesicles, which are then moved by axon
transport into the terminals, or varicosities where
the vesicle contents are cleaved by specific
peptidases.

• Many of the precursor proteins contain multiple


peptides, which may be different or copies of one
peptide.

• Neurons that release one or more of the peptide


neurotransmitters are collectively called
peptidergic.

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• In many cases, neuropeptides are co-secreted with
another type of neurotransmitter and act as
neuromodulators.

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Endorphine

• Certain neuropeptides, termed endogenous opioids


— beta-endorphin, the dynorphins, and the
enkephalins—have attracted much interest because
their receptors are the sites of action of opiate
drugs such as morphine and codeine.

• The opiate drugs are powerful analgesics (that is,


they relieve pain without loss of consciousness),
and the endogenous opioids undoubtedly play a
role in regulating pain.

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• The opioids have been implicated in the runner’s
“second wind,” when the athlete feels a boost of
energy and a decrease in pain and effort, and in the
general feeling of wellbeing experienced after a
bout of strenuous exercise, the so-called jogger’s
high.

• There is also evidence that the opioids play a role in


eating and drinking behavior, in regulation of the
cardiovascular system, and in mood and emotion.

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Substance P

• Substance P, another of the neuropeptides, is a


transmitter released by afferent neurons that relay
sensory information into the central nervous
system.

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NO

• Surprisingly, at least one gas—nitric oxide—serves as


a neurotransmitter.
• Gases are not released from presynaptic vesicles,
nor do they bind to postsynaptic plasma-membrane
receptors. They simply diffuse from their sites of
origin in one cell into the intracellular fluid of
nearby cells.

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• Nitric oxide serves as a messenger between some
neurons, and between neurons and effector cells.
• It is produced in one cell from the amino acid
arginine (in a reaction catalyzed by nitric oxide
synthase),
• and it binds to and activates guanylyl cyclase in the
recipient cell, thereby increasing the concentration
of the second-messenger cyclic GMP in that cell

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• Nitric oxide plays a role in a bewildering array of
neurally mediated events—learning, development,
drug tolerance, penile erection, and sensory and
motor modulation, to name a few.

• Paradoxically, it is also implicated in neural damage


that results, for example, from the stoppage of
blood flow to the brain or from a head injury.

• It is produced by a variety of non-neural cells as


well, and plays an important paracrine role in the
cardiovascular and immune systems, among
others.
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ATP

• Another surprise is that ATP, the molecule that


serves as an important energy source, is
also a neurotransmitter, as is adenine, the purine
base from which ATP is formed.
• Like glutamate, ATP is a very fast acting excitatory
transmitter

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Summary

• The neurotransmitters released by these efferent


neurons’ terminals or varicosities, provide the link
by which electrical activity of the nervous system is
able to regulate effector cell activity.

• The events that occur at neuroeffector junctions are


similar to those at a synapse. The neurotransmitter
is released from the efferent neuron upon the
arrival of an action potential at the neuron’s axon
terminals or varicosities.

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• The neurotransmitter then diffuses to the surface of
the effector cell, where it binds to receptors on that
cell’s plasma membrane.

• The receptors may be directly under the axon


terminal or varicosity, or they may be some
distance away so that the diffusion path followed by
the neurotransmitter is tortuous and long.

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• The receptors on the effector cell may be associated
with ion channels that alter the membrane potential of
the cell, or

• they may be coupled via a G protein, to enzymes that


result in the formation of second messengersin the
effector cell.

• The response (altered muscle contraction or


glandular secretion) of the effector cell to these
changes will be described in later chapters.

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Monday, November 27, 17