Download - neuron structure and function
1
Definition
A chemical released by one neuron that affects another
neuron or an effector organ
(e.g., muscle, gland, blood vessel)
3
4
Neurotransmitters
Properties Synthesized in the presynaptic neuron Localized to vesicles in the presynaptic
neuron Released from the presynaptic neuron
under physiological conditions Rabidly removed from the synaptic cleft by
uptake or degradation Presence of receptor on the post-synaptic
neuron Binding to the receptor elicits a biological
response
R.E.B, 4MedStudents.com, 2003
5
6
7
Neurotransmitters found in the nervous system
EXCITATORY
Acetylcholine
Aspartate
Dopamine
Histamine
Norepinephrine
Epinephrine
Glutamate
Serotonin
INHIBITORY
GABA
Glycine
8
9
10
Fate of neurotransmitters Are as ,1. It is consumed ( broken down or used
up) at postsynaptic membrane leading to action potential generation.
2. Degraded by enzymes present in synaptic cleft.
3. Reuptake mechanism( reutilization) this is the most common fate.
11
Types of responses on postsynaptic membrane
Excitatory postsynaptic potential (EPSPs)
It is caused by depolarization. Inhibitory Postsynaptic potential
(IPSPs)It is caused by hyperpolarization.
12
Fast & Slow Postsynaptic potentials
Fast EPSPs & IPSPs work through ligand gated ion channels.eg. Nicotinic receptors(at the level of neuromuscular junction)
Slow EPSPs & IPSPs are produced by multi step process involving G protein eg. Muscarinic receptors ( at the level of autonomic gangila)
13
EPSP
Excitatory Postsynaptic Potential
Membrane depolarizes
Result from opening of chemically gated cation channels
Allow Na+, K+, Ca++ to pass into the neuron
Na+ in flow is greater than Ca++ inflow or K+ outflow
Electrical and concentration gradients promote inflow
14
IPSP
Inhibitory Postsynaptic Potential
Membrane hyperpolarizes
Increases membrane potential by making inside more negative
Generation of nerve impulse more difficult
Often result from opening chemically gated Cl- or K+ channels
Inside becomes more negative by Cl- inflow or increased K+ outflow
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
Release of acetylcholine from presynaptic neurons:
1)When the nerve impulse (Action potential) moves down the presynaptic axon to the terminal bulb the change in the membrane action potential causes the opening of voltage gated calcium channels open allowing Ca2+
ions to pass from the synaptic cleft into the axon bulb.
2) Within the bulb the increase in Ca2+ concentration causes the synaptic vesicles that contain acetylcholine to fuse with the axonal membrane and open spilling their contents into the synaptic cleft.
17
Binding of acetylcholine to the postsynaptic receptors:
The postsynaptic membrane of the receptor dendrite has specific cholinergic receptors toward which the neurotransmitter diffuses. Binding of acetylcholine trigger the opening of ion channels in the postsynaptic membrane initiating action potential that can pass in the next axon
Acetylcholine receptors are ion channels receptors made of many subunits arranged in the form [(α2)(β)(γ)(δ)]
Binding of two acetylcholine molecules to the receptors will rotate the subunits in which the smaller polar residues will line the ion channel causing the influx of Na+ into the cell and efflux of K+ resulting in a depolarization of the postsynaptic neuron and the initiation of new action potential
18
Removal of Acetylcholine from the synaptic cleft:
In order to ready the synapse for another impulses: 1) The neurotransmitters, which are released from the synaptic vesicles, are
hydrolyzed by enzyme present in the synaptic cleft “Acetylcholinestrase” giving choline, which poorly binds to acetylcholine receptors.
Acetylcholine + H2O Choline + H+ acetate
2) The empty synaptic vesicles, which are returned to the axonal terminal bulb by endocytosis, must be filled with acetylecholine.
AcetylcholinestraseAcetylcholinestrase
19
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.
20
Catecholamine Synthesis (Dopamine, Norepinephrine and Epinephrine).
1) First Step: Hydroxylation: In this step: the reaction involves the conversion of tyrosine, oxygen
and tetrahydrobiopterin to dopa & dihydrobiopterin. This reaction is catalyzed by the enzyme tyrosine hydroxylase. It is irreversible reaction.
2) Second step: Decarboxylation: In this step: the dopa decaboxylase will catalyze the decaoxylation of
dopa to produce dopamine. The deficiency of this enzyme can cause Parkinson’s disease. It is irreversible reaction. The cofactor in this reaction is the PLP (pyridoxal phosphate). In the nerve cells that secrete dopamine as neurotransmitter the pathway ends at this step.
21
3) Third step: Hydroxylation:
This reaction is catalyzed by the enzyme dopamine β- hydroxylase. The reactants include dopamine, O2 and ascorbate (vitamin C).
The products are norepinephrine, water and dehydroascorbate. It is an irreversible reaction). The end product in noradrenergic cells is norepinephrine and the pathway ends her.
4) Forth step: Methylation:
This reaction is catalyzed by phenylethanolamine N-methyltransferase. Norepinephrine and S-adenosylmethionin (ado-Met) form epinephrine and S-adenosyl homocysteine (ado-Hcy).
Catecholamine Synthesis (Dopamine, Norepinephrine and Epinephrine).
22
23
Serotonin synthesis:
•Serotonin is synthesized from the amino acid Tryptophan.
•The synthesis of serotonin involve two reactions:
1) 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.
2) 2) Decarboxylation:
5- hydroxytryptophan Serotonin
The enzyme is hydroxytryptophan decarboxylase.
•Serotonin is synthesized in CNS, & Chromaffin cells.
24
25
Break down of serotonin: Serotonin is degraded in two reactions
1) Oxidation:1) Oxidation:5-hydroxytryptoamine + O2 + H2O 5-
Hydroxyinodole-3-acetaldehyde
2) Dehydrogenation2) Dehydrogenation5- Hydroxyinodole-3-acetaldehyde 5-hydroxindole-3-
acetate
(Anion of 5-hydroxyindoleacetic acid)
Monoamine oxidase
Aldehyde dehydrogenase
26
NeurotransmitterPostsynaptic
effectDerived from
Site of synthesis
Postsynaptic receptor
Fate Functions
1.Acetyl choline(Ach)
Excitatory Acetyl co-A +Choline
Cholinergic nerve endingsCholinergic pathways of brainstem
1.Nicotinic2.Muscarinic
Broken by acetyl cholinesterase
Cognitive functions e.g. memoryPeripheral action e.g. cardiovascular system
2. Catecholaminesi. Epinephrine (adrenaline)
Excitatory in some but inhibitory in other
Tyrosine produced in liver from phenylalanine
Adrenal medulla and some CNS cells
Excites both alpha α &beta β receptors
1.Catabolized to inactive product through COMT & MAO in liver2.Reuptake into adrenergic nerve endings3.Diffusion away from nerve endings to body fluid
For details refer ANS. e.g. fight or flight, on heart, BP, gastrointestinal activity etc. Norepinehrine controls attention & arousal.
ii.Norepinephrine Excitatory Tyrosine, found in pons. Reticular formation, locus coerules, thalamus, mid-brain
Begins inside axoplasm of adrenergic nerve ending is completed inside the secretary vesicles
α1 α2
β1 β2
iii. Dopamine Excitatory Tyrosine CNS, concentrated in basal ganglia and dopamine pathways e.g. nigrostriatal, mesocorticolimbic and tubero-hypophyseal pathway
D1 to D5
receptor
Same as above Decreased dopamine in parkinson’s disease.Increased dopamine concentration causes schizophrenia
27
NeurotransmitterPostsynaptic
effectDerived from
Site of synthesis
Postsynaptic receptor
Fate Functions
3. serotonin(5HT)
Excitatory Tryptophan CNS, Gut (chromaffin cells) Platelets & retina
5-HT1 to 5-HT
7
5-HT 2 A
receptor mediate platelet aggregation & smooth muscle contraction
Inactivated by MAO to form 5-hydroxyindoleacetic acid(5-HIAA) in pineal body it is converted to melatonin
Mood control, sleep, pain feeling, temperature, BP, & hormonal activity
4. Histamine Excitatory Histidine Hypothalamus Three types H1,
H2 ,H3 receptors
found in peripheral tissues & the brain
Enzyme diamine oxidase (histaminase) cause breakdown
Arousal, pain threshold, blood pressure, blood flow control, gut secretion, allergic reaction (involved in sensation of itch)
5. Glutamate Excitatory75% of excitatory transmission in the brain
By reductive amination of Kreb’s cycle intermediate α –ketoglutarate.
Brain & spinal cord e.g. hippocampus
Ionotropic and metabotropic receptors.Three types of ionotropic receptors e.g. NMDA, AMPA and kainate receptors.
It is cleared from the brain ECF by Na + dependent uptake system in neurons and neuroglia.
Long term potentiation involved in memory and learning by causing Ca++ influx.
28
NeurotransmitterPostsynaptic
effectDerived from
Site of synthesis
Postsynaptic receptor
Fate Functions
6. Aspartate Excitatory Acidic amines Spinal cord Spinal cordAspartate & Glycine form an excitatory / inhibitory pair in the ventral spinal cord
7. Gama amino butyric acid(GABA)
Major inhibitory mediator
Decarboxylation of glutamate by glutamate decarboxylase (GAD) by GABAergic neuron.
CNS
GABA – A increases the Cl - conductance, GABA – B is metabotropic works with G – protein GABA transaminase catalyzes. GABA – C found exclusively in the retina.
Metabolized by transamination to succinate in the citric acid cycle.
GABA – A causes hyperpolarization (inhibition) Anxiolytic drugs like benzodiazepine cause increase in Cl- entry into the cell & cause soothing effects. GABA – B cause increase conductance of K+ into the cell.
8. Glycine Inhibitory
Is simple amino acid having amino group and a carboxyl group attached to a carbon atom
Spinal cord
Glycine receptor makes postsynaptic membrane more permeable to Cl- ion.
Deactivated in the synapse by simple process of reabsorbtion by active transport back into the presynaptic membrane
Glycine is inhibitory transmitted found in the ventral spinal cord. It is inhibitory transmitter to Renshaw cells.
29
RECEPTORS DYSFUNCTION
1. Presynaptic effecti) Botulinum toxin: Its an exotoxin that
binds to the presynaptic membrane and prevents the release of Ach resulting in weakness and reduction of tone. It is used to control dystonia in which body shows overactive muscular activity.
30
ii) Lumbert – Eaton syndromeAntibodies directed against Ca++
channels located in presynaptic terminals and interfere with transmitter release causing weakness.
iii)NeuromyotoniaPatient complains of muscle spasm and
stiffness resulting in continuous motor activity in the muscle. It is cased by antibody directed against the presynaptic voltage gated K+ channel so that the nerve terminal is always in a state of depolarization
31
2. Effects at Postsynaptic level:i) Curare binds to the acetylcholine
receptor (AchR) and prevents Ach from acting on it and so that it induces paralysis.
ii) Myasthenia gravis: is caused by an antibody against the Ach receptors and Ach receptors are reduced hence the Ach released has few Ach receptor available to work and patients complain of weakness that increases with exercise.
32
INTRACELLULAR SIGNAL TRANSDUCTION OF SYNAPTIC NEUROTRANSMISSION
http://sites.sinauer.com/neuroscience5e/animations07.01.htmlhttp://sites.sinauer.com/neuroscience5e/animations07.02.html