NEUROBIOCHEMISTRY SYNAPSE AND NEUROTRANSMITTER MOHAMMAD HANAFI.

NEUROBIOCHEMISTRY

SYNAPSE

AND

NEUROTRANSMITTER

MOHAMMAD HANAFI

• 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

Synapses

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

Synapses

Figure 11.17

1. Axodendritic synapse

2. Axosomatic synapse3. Axoaxonic synapse

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.

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.

Chemical SynapseEvents at a chemical synapse1. 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 memb6. Receptor changes shape of ion channel opening it and changing membrane potential7. 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.

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.

Removal of Neurotransmitter from Synaptic Cleft

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.

Neurotransmitters found in the nervous system

EXCITATORY

Acetylcholine

Aspartate

Dopamine

Histamine

Norepinephrine

Epinephrine

Glutamate

Serotonin

INHIBITORY

GABA

Glycine

• 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

Neurotransmitters

• Acetylcholine (ACh)

• Biogenic amines

• Amino acids

• Peptides

• Novel messengers: ATP and dissolved gases NO and CO

Chemical Neurotransmitters

• 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

Neurotransmitters: Acetylcholine

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.

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.

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

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.

1. Acetylcholine is involved in a variety of functions including pain, recent memory, nicotine addiction,

salivation, locomotion, regulation of circadian rhythm and thermoregulation.

FUNCTIONS OF ACh

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.

• 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

Neurotransmitters: Biogenic Amines

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

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 Parkinson’s disease– May be involved in pathogenesis of schizophrenia

Serotonin (5-HT)

• Synthesized from a.a. tryptophan

The synthesis of serotonin involve two reactions:1) Hydroxylation:Tryptophan 5- HydroxytryptophanThe enzyme catalyzes this reaction is Tryptophan Hydroxylase. The Co- factor is Tetrahydrobiopterin, which converted in this reaction to Dihydrobiopterin

2) Decarboxylation:

5- hydroxytryptophan Serotonin

The enzyme is hydroxytryptophan decarboxylase.

Serotonin is synthesized in CNS, & Chromaffin cells.

Break down of serotonin:

• Serotonin is degraded in two recations

1) Oxidation:1) Oxidation:

5-hydroxytryptoamine + O2 + H2O 5- Hydroxyinodole-3-

acetaldehyde

2) Dehydrogenation2) Dehydrogenation

5- Hydroxyinodole-3-acetaldehyde 5-hydroxindole-3-acetate

(Anion of 5-hydroxyindoleacetic acid)

Monoamine oxidase

Aldehyde dehydrogenase 

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

• Include:– GABA – Gamma ()-aminobutyric acid – Glycine– Aspartate– Glutamate

• Found only in the CNS

Neurotransmitters: Amino Acids

Amino AcidsGABA

• 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!)

SYNTHESIS AND RELEASE OF GLUTAMATE

NMDA RECEPTOR

FUNCTIONS OF GLUTAMATE

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.

1. Glutamate acts as the major excitatory transmitter in the brain

SYNTHESIS AND RELEASE OF GABA

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

GABA

GABAA RECEPTOR

FUNCTIONS OF GABA

1. 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.

• 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

Neurotransmitters: Peptides

• 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

Neurotransmitters: Novel Messengers

Neurotransmitter Molecule

Derived From

Site of Synthesis

Acetylcholine Choline CNS, parasympathetic nerves

Serotonin5-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 synthesis pathway

Tyrosine CNS, sympathetic nerves

Dopamine synthesis pathway

Tyrosine CNS

Nitric oxide, NO Arginine CNS, gastrointestinal tract

Summary: