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neuron structure and function

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this is my course work presentation, one of the neurochemistry topic. Im PhD scholar from NUST. Pakistan.

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Page 2: neuron structure and function

Definition

A chemical released by one neuron that affects another

neuron or an effector organ

(e.g., muscle, gland, blood vessel)

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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

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Neurotransmitters found in the nervous system

EXCITATORY

Acetylcholine

Aspartate

Dopamine

Histamine

Norepinephrine

Epinephrine

Glutamate

Serotonin

INHIBITORY

GABA

Glycine

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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.

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Types of responses on postsynaptic membrane

Excitatory postsynaptic potential (EPSPs)

It is caused by depolarization. Inhibitory Postsynaptic potential

(IPSPs)It is caused by hyperpolarization.

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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)

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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

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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

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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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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.

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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

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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

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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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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.

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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).

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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.

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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 

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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

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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

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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.

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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.

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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.

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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

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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.

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INTRACELLULAR SIGNAL TRANSDUCTION OF SYNAPTIC NEUROTRANSMISSION

http://sites.sinauer.com/neuroscience5e/animations07.01.htmlhttp://sites.sinauer.com/neuroscience5e/animations07.02.html