NEUROBIOCHEMISTRY

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NEUROBIOCHEMISTRY

• SYNAPSE
• AND
• NEUROTRANSMITTER

MOHAMMAD HANAFI
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Synapses

• A junction that mediates information transfer
  from one neuron
• To another neuron
• To an effector cell
• Presynaptic neuron conducts impulses toward the
  synapse
• Postsynaptic neuron transmits impulses away
  from the synapse

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The Synapse

• Junction between two cells
• Site where action potentials in one cell cause
  action potentials in another cell
• Types of cells in synapse
• Presynaptic
• Postsynaptic

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Synapses

1. Axodendritic synapse
2. Axosomatic synapse
3. Axoaxonic synapse

Figure 11.17
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Electrical Synapses

• Gap junctions that allow local current to flow
  between adjacent cells. Connexons protein tubes
  in cell membrane.
• Found in cardiac muscle and many types of smooth
  muscle. Action potential of one cell causes
  action potential in next cell, almost as if the
  tissue were one cell.
• Important where contractile activity among a
  group of cells important.

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Chemical Synapses

• Components
• Presynaptic terminal
• Synaptic cleft
• Postsynaptic membrane
• Neurotransmitters released by action potentials
  in presynaptic terminal
• Synaptic vesicles action potential causes Ca 2
  to enter cell that causes neurotransmitter to be
  released from vesicles
• Diffusion of neurotransmitter across synapse
• Postsynaptic membrane when ACh binds to
  receptor, ligand-gated Na channels open. If
  enough Na diffuses into postsynaptic cell, it
  fires.

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Chemical Synapse

• Events at a chemical synapse
• 1. Arrival of nerve impulse opens
• volage-gated calcium channels.
• 2. Ca influx into presynaptic term.
• 3. Ca acts as intracellular messenger
• stimulating synaptic vesicles to fuse with
• membrane and release NT via exocytosis.
• 4. Ca removed from terminal by
• mitochondria or calcium-pumps.
• 5. NT diffuses across synaptic cleft and
• binds to receptor on postsynaptic memb
• 6. Receptor changes shape of ion channel
• opening it and changing membrane potential
• 7. NT is quickly destroyed by enzymes or
• taken back up by astrocytes or presynaptic
• membrane.
• Note For each nerve impulse reaching the
  presynaptic terminal, about 300 vesicles are
  emptied into the cleft.

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Neurotransmitter Removal

• Method depends on neurotransmitter/synapse.
• ACh acetylcholinesterase splits ACh into acetic
  acid and choline. Choline recycled within
  presynaptic neuron.
• Norepinephrine recycled within presynaptic
  neuron or diffuses away from synapse. Enzyme
  monoamine oxidase (MAO). Absorbed into
  circulation, broken down in liver.

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Removal of Neurotransmitter from Synaptic Cleft
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Receptor Molecules and Neurotransmitters

• Neurotransmitter only "fits" in one receptor.
• Not all cells have receptors.
• Neurotransmitters are excitatory in some cells
  and inhibitory in others.
• Some neurotransmitters (norepinephrine) attach to
  the presynaptic terminal as well as postsynaptic
  and then inhibit the release of more
  neurotransmitter.

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Neurotransmitters found in the nervous system
EXCITATORY Acetylcholine Aspartate Dopamine Hi
stamine Norepinephrine Epinephrine Glutamate S
erotonin INHIBITORY GABA Glycine
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Neurotransmitters

• Chemicals used for neuronal communication with
  the body and the brain
• 50 different neurotransmitters have been
  identified
• Classified chemically and functionally
• Chemically
• ACh, Biogenic amines, Peptides
• Functionally
• Excitatory or inhibitory
• Direct/Ionotropic (open ion channels) or
  Indirect/metabotropic (activate G-proteins) that
  create a metabolic change in cell

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Chemical Neurotransmitters

• Acetylcholine (ACh)
• Biogenic amines
• Amino acids
• Peptides
• Novel messengers ATP and dissolved gases NO and
  CO

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Neurotransmitters Acetylcholine

• First neurotransmitter identified, and best
  understood
• Released at the neuromuscular junction
• Synthesized and enclosed in synaptic vesicles
• Degraded by the enzyme acetylcholinesterase
  (AChE)
• Released by
• All neurons that stimulate skeletal muscle
• Some neurons in the autonomic nervous system
• Binds to cholinergic receptors known as nicotinic
  or muscarinic receptors
• Nicotinic receptors
• Neuromuscular junction of skeletal muscles

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Acetylcholine synthesis

• In the cholinergic neurons acetylcholine is
  synthesized from choline. This reaction is
  activated by cholineacetyltransferase

As soon as acetylcholine is synthesized, it is
stored within synaptic vesicles.
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Structure of AchE

• Acetylcholinesterase (AchE) is an enzyme, which
  hydrolyses the neurotransmitter acetylcholine.
  The active site of AChE is made up of two
  subsites, both of which are critical to the
  breakdown of ACh. The anionic site serves to bind
  a molecule of ACh to the enzyme. Once the ACh is
  bound, the hydrolytic reaction occurs at a second
  region of the active site called the esteratic
  subsite. Here, the ester bond of ACh is broken,
  releasing acetate and choline. Choline is then
  immediately taken up again by the high affinity
  choline uptake system on the presynaptic
  membrane.

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Cholinergic Receptors

• Nicotinic receptors
• - On neuromuscular junction of skeletal muscle
• - On all ganglionic neurons of autonomic nervous
  system
• - Excitatory
• Muscarinic receptors
• - All parasympathetic target organs (cardiac and
  smooth
• muscle)
• - Exciatory in most cases

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Acetylcholine

• Effects prolonged (leading to tetanic muscle
  spasms and neural frying) by nerve gas and
  organophosphate insecticides (Malathion).
• ACH receptors destroyed in myasthenia gravis
• Binding to receptors inhibited by curare (a
  muscle paralytic agent-blowdarts in south
  American tribes) and some snake venoms.

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FUNCTIONS OF ACh

• Acetylcholine is involved in a variety of
  functions
• including pain, recent memory, nicotine
  addiction, salivation, locomotion, regulation of
  circadian rhythm and thermoregulation.

2. It has also been demonstrated that brain
cholinergic neurons play a critical role in
Alzheimers disease, Huntingtons chorea and in
the generation of epileptic seizures.
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Neurotransmitters Biogenic Amines

• Include
• Catecholamines dopamine, norepinephrine (NE),
  and epinephrine (EP)
• Indolamines serotonin and histamine
• Broadly distributed in the brain
• Play roles in emotional behaviors and our
  biological clock

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Synthesis of Catecholamines

• AA tyrosine parent cpd
• Enzymes present in the cell determine length of
  biosynthetic pathway
• Norepinephrine and dopamine are synthesized in
  axonal terminals
• Epinephrine is released by the adrenal medulla as
  a hormone

Figure 11.22
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BIOGENIC AMINES

• Norepinephrine (aka 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
• Dopamine
• Binds to dopaminergic receptors of substantia
  nigra of midbrain and hypothalamus
• Feeling good NT
• Release enhanced by amphetamines
• Reuptake block by cocaine
• Deficient in Parkinsons disease
• May be involved in pathogenesis of
  schizophrenia

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Serotonin (5-HT)

• Synthesized from a.a. tryptophan

The synthesis of serotonin involve two
reactions 1) Hydroxylation Tryptophan 5-
Hydroxytryptophan The enzyme catalyzes this
reaction is Tryptophan Hydroxylase. The Co-
factor is Tetrahydrobiopterin, which converted in
this reaction to Dihydrobiopterin
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2) Decarboxylation 5- hydroxytryptophan
Serotonin The enzyme is hydroxytryptophan
decarboxylase. Serotonin is synthesized in CNS,
Chromaffin cells.
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Break down of serotonin

• Serotonin is degraded in two recations
• 1) Oxidation
• 5-hydroxytryptoamine O2 H2O
• 5- Hydroxyinodole-3-
• 
  acetaldehyde
• 2) Dehydrogenation
• 5- Hydroxyinodole-3-acetaldehyde
  5-hydroxindole-3-acetate
  
  (Anion of 5-hydroxyindoleacetic acid)

• Aldehyde dehydrogenase 

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May play a role in sleep, appetite, and
regulation of moods Drugs that block its uptake
relieve anxiety and depression SSRIs
selective serotonin reuptake inhibitors
Include drugs such as Prozac, Celexa, Lexapro,
Zoloft
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Neurotransmitters Amino Acids

• Include
• GABA Gamma (?)-aminobutyric acid
• Glycine
• Aspartate
• Glutamate
• Found only in the CNS

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Amino Acids

• GABA
• Main inhibitory neurotransmitter in the brain
• Inhibitory effects augmented by alcohol and
  antianxiety drugs like Valium
• Increases influx of Cl- in postsynaptic neuron,
• hyperpolarising it and thus inhibiting it!
• GLUTAMATE
• Widespread in brain where it represents
  the major
• excitatory neurotransmitter
• Important in learning and memory
• Stroke NT -excessive release produces
  excitotoxicity
• neurons literally stimulated to death most
  commonly
• caused by ischemia due to stroke (Ouch!)
• Aids tumor advance when released by gliomas
  (ouch!)

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SYNTHESIS AND RELEASE OF GLUTAMATE
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NMDA RECEPTOR
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FUNCTIONS OF GLUTAMATE
1. Glutamate acts as the major excitatory
transmitter in the brain
2. Excess glutamate causes neuronal damage and
death, principally by elevating cellular
Ca2. This phenomenon has significance for a
number of pathologies such as Alzheimers
disease, ALS, Ischemia and Hypoxia, Epilepsy
and Schizophrenia.
3. Glutamate receptors are involved in a
physiological phenomenon called long-term
potentiation (LTP) - a cellular model of
learning and memory. The NMDA receptor
activation is an absolute requirement for LTP
induction, however, AMPA and metabotropic
glutamate receptors also play important roles.
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SYNTHESIS AND RELEASE OF GABA
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GABA
Gambar 46. Metabolisme ? amino butirat
Catatan PLP piridoksal fosfat.
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GABAA RECEPTOR
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FUNCTIONS OF GABA

• GABA acts as the major inhibitory transmitter
• in the brain

2. GABA has been implicated in several
neurological and psychiatricdisorders of
humans including Huntingtons chorea,
epilepsy, alcoholism, Parkinsons disease and
anxiety disorders.
3. Antiepileptic and anxiolytic properties of
benzodiazepine and phenobarbital suggest an
important role of GABA in epilepsy as well as
anxiety disorders.
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Neurotransmitters Peptides

• Include
• Substance P mediator of pain signals
• Beta endorphin, dynorphin, and enkephalins
• Act as natural opiates, reducing our perception
  of pain
• Found in higher concentrations in marathoners and
  women who have just delivered
• Bind to the same receptors as opiates and
  morphine

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Neurotransmitters Novel Messengers

• Nitric oxide (NO)
• A short-lived toxic gas diffuses through
  post-synaptic membrane to bind with intracellular
  receptor (guanynyl cyclase)
• Is involved in learning and memory
• Some types of male impotence treated by
  stimulating NO release (Viagra)
• Viagra ? NO release ? cGMP ? smooth muscle
  relaxation ? increased blood flow ? erection
• Cant be taken when other pills to dilate
  coronary b.v. taken
• Carbon monoxide (CO) is a main regulator of cGMP
  in the brain

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Summary