1. SYNAPSE AND NEUROTRANSMITTER
NEUROBIOCHEMISTRY
SYNAPSE
AND
NEUROTRANSMITTER
MOHAMMAD HANAFI

2. 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

3. 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

4. Synapses Axodendritic synapse Axosomatic synapse Axoaxonic synapse
Figure 11.17

5. 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.

6. 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.

7. 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.

8. 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.

9. Removal of Neurotransmitter from Synaptic Cleft

10. 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.

11. Neurotransmitters found in the nervous system
EXCITATORY
Acetylcholine
Aspartate
Dopamine
Histamine
Norepinephrine
Epinephrine
Glutamate
Serotonin
INHIBITORY
GABA
Glycine

12. 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

13. Chemical Neurotransmitters
Acetylcholine (ACh)
Biogenic amines
Amino acids
Peptides
Novel messengers: ATP and dissolved gases NO and CO

14. 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

15. 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.

16. 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.

19. 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

20. 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.

21. 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
Alzheimer’s disease, Huntington’s chorea and in
the generation of epileptic seizures.

22. 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

23. 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

24. BIOGENIC AMINES Norepinephrine (aka Noradrenaline) Dopamine
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
Reuptake block by cocaine
Deficient in Parkinson’s disease
May be involved in pathogenesis of schizophrenia

25. Synthesized from a.a. tryptophan
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

26. 2) Decarboxylation: 5- hydroxytryptophan Serotonin
The enzyme is hydroxytryptophan decarboxylase.
Serotonin is synthesized in CNS, & Chromaffin cells.

27. 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 hydroxindole-3-acetate (Anion of 5-hydroxyindoleacetic acid)
Monoamine oxidase
Aldehyde dehydrogenase 

28. May play a role in sleep, appetite, and
regulation of moods
Drugs that block its uptake relieve
anxiety and depression
SSRI’s = selective serotonin reuptake
inhibitors
Include drugs such as Prozac,
Celexa, Lexapro, Zoloft

29. Neurotransmitters: Amino Acids
Include:
GABA – Gamma ()-aminobutyric acid
Glycine
Aspartate
Glutamate
Found only in the CNS

30. 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!)

31. SYNTHESIS AND RELEASE OF GLUTAMATE

33. NMDA RECEPTOR

34. 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 Ca+2. This phenomenon
has significance for a number of pathologies such as
Alzheimer’s 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.

35. SYNTHESIS AND RELEASE OF GABA

36. GABA
Gambar 46. Metabolisme γ amino butirat
Catatan: PLP = piridoksal fosfat.

37. GABAA RECEPTOR

38. GABA acts as the major inhibitory transmitter in the brain
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 Huntington’s
chorea, epilepsy, alcoholism, Parkinson’s 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.

39. 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

40. 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
Can’t be taken when other pills to dilate coronary b.v. taken
Carbon monoxide (CO) is a main regulator of cGMP in the brain

41. Summary: Neurotransmitter Molecule Derived From Site of Synthesis
Acetylcholine
Choline
CNS, parasympathetic nerves
Serotonin 5-Hydroxytryptamine (5-HT)
Tryptophan
CNS, chromaffin cells of the gut, enteric cells
GABA
Glutamate
CNS
Histamine
Histidine
hypothalamus
Epinephrine
synthesis pathway
Tyrosine
adrenal medulla, some CNS cells
Norpinephrine
CNS, sympathetic nerves
Dopamine
Nitric oxide, NO
Arginine
CNS, gastrointestinal tract