Neurotransmission Azam Basheer MD

NeurotransmissionNeurotransmission

Azam Basheer MDAzam Basheer MDHenry Ford NeurosurgeryHenry Ford Neurosurgery

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Resting potentialResting potential

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Resting potentialResting potential

There is a potential difference between the inside and outside of as membrane. The inside is about -70 mv relative to the outside.

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Resting PotentialResting PotentialThe resting potential is caused by an uneven distribution of ions (electrically charged molecules) of potassium (K+) and sodium (Na+) and chloride (Cl-).

This is caused by Na+/K+ ion pumps that move 3 Na+ ions out of the cell for every 2 K+ ions it moves in.

Therefore there are more +ions outside the cell than inside and the inside is negatively charged with respect to the outsideAzam Basheer

Ion pumpIon pump

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Ion channelsIon channels

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Action potentialAction potential

► Anything that alters the functioning of the Anything that alters the functioning of the ion channels can change the resting ion channels can change the resting potential.potential.

► If changes cause the resting potential to If changes cause the resting potential to be reduced, this is called be reduced, this is called depolarization.depolarization.

► If the change causes an increase in the If the change causes an increase in the resting potential, this is caused resting potential, this is caused hyperpolarizationhyperpolarization..

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► Voltage gated ion channels open and let Na+ into Voltage gated ion channels open and let Na+ into the cell. They are driven into the cell because of the cell. They are driven into the cell because of diffusion gradient and electrostatic charge.diffusion gradient and electrostatic charge.

► This causes the resting potential to reverse, i.e., the This causes the resting potential to reverse, i.e., the inside the cell becomes positive.inside the cell becomes positive.

► Now the Na+ ion channels close and the K+ Now the Na+ ion channels close and the K+ channels open and the K+ ions are driven out of the channels open and the K+ ions are driven out of the cell because of their concentration gradient and cell because of their concentration gradient and electrostatic charge. electrostatic charge.

► Finally the K+ channels close and the ion pumps Finally the K+ channels close and the ion pumps kick in and the resting potential returns to normal.kick in and the resting potential returns to normal.

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All or None LawAll or None Law

►Action potentials when they occur are Action potentials when they occur are always the same. always the same.

►Once the process is initiated, it must Once the process is initiated, it must run its course and nothing can stop it run its course and nothing can stop it or change itor change it

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Transmission of action Transmission of action potentials along a membranepotentials along a membrane

►When an action potential occurs at one When an action potential occurs at one place on the membrane of an axon, place on the membrane of an axon, the surrounding membrane is the surrounding membrane is depolarized past threshold causing an depolarized past threshold causing an action potential. This depolarizes the action potential. This depolarizes the neighboring membrane, etc. neighboring membrane, etc.

►Action potentials sweep across a Action potentials sweep across a membrane as fast as 100m/secmembrane as fast as 100m/sec

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2 ) How does Botox work?A) Inactivates AchEB) Binds directly to the Ach receptor on the post-synaptic membraneC) Generates antibodies directed against Ca++ channels located in ntibodies directed against Ca++ channels located in presynaptic terminalspresynaptic terminals D) Prevents the synaptic vesicle from exocytosis by degrading SNARE docking protein

1) Which of the following will produce an EPSP?A) opening a sodium channelB) closing a sodium channelC) opening a potassium channelD) closing a calcium channel

Questions

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A junction that mediates information A junction that mediates information transfer from one cell to another, transfer from one cell to another, usually from one neuron:usually from one neuron: To another neuronTo another neuron To an effector cell (i.e. sweat gland, To an effector cell (i.e. sweat gland,

muscle cell)muscle cell)

SynapsesSynapses

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Types of SynapsesTypes of Synapses

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Electrical SynapsesElectrical Synapses

Gap junctions Gap junctions made up of made up of protein channels in the protein channels in the cell membrane called cell membrane called ConnexonsConnexons allow allow Bi-Bi-directionaldirectional flow of flow of current between current between adjacent cells. adjacent cells.

Found in cardiac and Found in cardiac and smooth muscle. Action smooth muscle. Action potential of one cell potential of one cell causes action potential in causes action potential in next cell.next cell.

Important in synchronized Important in synchronized contractile activity.contractile activity.

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Chemical SynapsesChemical Synapses

presynaptic membrane

postsynaptic membrane

synaptic cleft

Uses Uses NeurotransmittNeurotransmitters released by ers released by action action potentials to potentials to transmit signalstransmit signals

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Structure of a synapseStructure of a synapse

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From electrical to chemicalFrom electrical to chemical

1. Precursor transport1. Precursor transport

2. NT synthesis2. NT synthesis

3. Storage3. Storage

4. Release4. Release

5. Activation5. Activation

6. Termination 6. Termination

Synaptic Transmission Synaptic Transmission ModelModel

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PresynapticAxon Terminal

PostsynapticMembrane

Terminal Button

Dendritic Spine

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1. Precursor Transport

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E

2. Synthesis

Enzymes & cofactors

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Synapse

Terminal Button Dendritic

Spine

3. StorageIn vesicles

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Synapse

Ca++

AP

4. Release • via exocytosis• diffusion

Arrival of nerve impulse opens volage-gated calcium channels

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Structure of the synapseStructure of the synapse

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Exocytosis: Membrane FusionExocytosis: Membrane Fusion

Ca2+ influx Ca2+ influx 2d 2d messenger Calmodulinmessenger Calmodulin

SNAPs: attachment SNAPs: attachment proteinsproteins

SNAREs: SNAP receptorsSNAREs: SNAP receptors

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5. Activation NT binds to receptorNT binds to receptor

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6. Termination

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1. Diffusion1. Diffusion2. Enzymatic 2. Enzymatic degradationdegradation3. Presynaptic 3. Presynaptic reuptakereuptake

4. 4. AutoreceptorAutoreceptorss

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3322

11

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ReceptorsReceptors

• neurotransmitter specific postsynaptic receptors

• open to allow ions to flow into the postsynaptic neuron

• two main types•ionotropic•metabotropic

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Neurotransmitter Neurotransmitter bindingbinding changes the receptor’s shape to open an ion changes the receptor’s shape to open an ion channel directlychannel directly

Fast acting and short lasting

Ionotropic receptors (ligand-Ionotropic receptors (ligand-gated)gated)

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Metabotropic receptors (G-Metabotropic receptors (G-protein)protein)

• indirect method• located nearby G-proteins• G-proteins in turn

activate an ion channel• slower to begin and

longer lasting

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Metabotropic receptorsMetabotropic receptors

Second Messenger Cascade:G-proteins can activate

second messengers – enzymes that in turn activate an ion channel

Second messenger Second messenger molecules can activate a molecules can activate a kinasekinase which lasts for which lasts for minutes and hours.minutes and hours.

Kinases can activate Kinases can activate transcription factorstranscription factors (CREB and c-fos) which (CREB and c-fos) which alter the expression of alter the expression of genes.genes.

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Post synaptic potentialPost synaptic potential

►Is the change in the resting potential Is the change in the resting potential ((depolarization or hyperpolarization) caused by caused by the activation of a receptorthe activation of a receptor

Inhibitory post synaptic potential (IPSP) – Inhibitory post synaptic potential (IPSP) – hyperpolarizes the cell making harder to fire hyperpolarizes the cell making harder to fire

►K+ K+ outout of cell of cell►Or Cl- Or Cl- intointo cell cell

Excitatory post synaptic potential (EPSP) – Excitatory post synaptic potential (EPSP) – depolarizing the cell making it more excitable depolarizing the cell making it more excitable

►Na+ Na+ intointo cell cellAzam Basheer

Postsynaptic Ion motionPostsynaptic Ion motion

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SummationSummation

Excitatory and inhibitory Excitatory and inhibitory potentials canpotentials can summate summate both in time (both in time (temporal temporal summationsummation) and across ) and across the membrane (the membrane (spatial spatial

summationsummation))

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Axoaxonic SynapsesAxoaxonic Synapses► Modulate NT releaseModulate NT release

via via or or Ca Ca2+ 2+

influxinflux► Via modulation of EVia modulation of Emm

CaCa2+2+, K, K++, and Cl, and Cl- -

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NeurotransmittersNeurotransmitters


NEUROTRANSMITTERSNEUROTRANSMITTERS

Chemical transducers Chemical transducers released by electrical released by electrical impulses into the impulses into the synaptic cleft leading to synaptic cleft leading to alteration in electrical alteration in electrical signalssignals

50 different 50 different neurotransmitters have neurotransmitters have been identifiedbeen identified

Loewi, 1921Loewi, 1921Azam Basheer

EXCITATORYAcetylcholineAspartateDopamineHistamine

NorepinephrineEpinephrineGlutamateSerotonin

INHIBITORYGABA Glycine

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► First neurotransmitter identifiedFirst neurotransmitter identified► Synthesized and enclosed in synaptic Synthesized and enclosed in synaptic

vesiclesvesicles

► DegradationDegradation

AcetylcholineAcetylcholine

Acetylcholine Choline + Acetate

Acetylcholine Esterase (AchE)

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Two types:- Muscarinc - Nicotinic

Binding of two Ach molecules will rotate the subunits 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.

Ach ReceptorAch Receptor

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Where it is FoundWhere it is Found

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NicotinicNicotinic MuscarinicMuscarinic11 Found at:Found at:

i.i. Neuromuscular junction of Neuromuscular junction of skeletalskeletal muscle muscle

ii.ii. ALLALL preganglionicpreganglionic neurons of the ANSneurons of the ANS

iii.iii. Ventral tegmental area.Ventral tegmental area.

i.i. Neuromuscular junctions Neuromuscular junctions of of cardiac cardiac andand smooth smooth muscle.muscle.

ii.ii. Some postganglionic Some postganglionic neurons of sympathetic neurons of sympathetic nervous system (sweat nervous system (sweat glands)glands)

22 AgonistAgonist NicotineNicotine Muscarine ( a toxin produced by Muscarine ( a toxin produced by certain mushroom)certain mushroom)

33 AntagonistAntagonist Curare ( paralyses skeletal Curare ( paralyses skeletal muscle)muscle)

AtropineAtropine

Acetylcholine ReceptorsAcetylcholine Receptors

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RECEPTORS DYSFUNCTIONRECEPTORS DYSFUNCTION

Presynaptic levelPresynaptic level

• Botulinum toxin: an exotoxin that binds to the Botulinum toxin: an exotoxin that binds to the presynaptic membrane and prevents the release of presynaptic membrane and prevents the release of Ach resulting in weakness and reduction of toneAch resulting in weakness and reduction of tone

• Black widow spider venom: Black widow spider venom: stimulates release of Ach

• Lambert – Eaton syndrome: Antibodies directed Lambert – Eaton syndrome: Antibodies directed against Caagainst Ca++++ channels located in presynaptic channels located in presynaptic terminals and interfere with transmitter release terminals and interfere with transmitter release causing weaknesscausing weakness

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Postsynaptic levelPostsynaptic level

1.1. Curare binds to the acetylcholine nicotinic Curare binds to the acetylcholine nicotinic receptors inducing paralysis.receptors inducing paralysis.

2.2. Myasthenia gravis: antibody against Ach Myasthenia gravis: antibody against Ach receptors and Ach receptors are reduced hence receptors and Ach receptors are reduced hence the Ach released has few Ach receptor available the Ach released has few Ach receptor available to work and patients complain of weakness that to work and patients complain of weakness that increases with exerciseincreases with exercise

3.3. Insecticides/Organophosphates/Sarin: inhibit Insecticides/Organophosphates/Sarin: inhibit AchE (Pralidoxime and atropine used as antidote)AchE (Pralidoxime and atropine used as antidote)

RECEPTORS DYSFUNCTION cont.RECEPTORS DYSFUNCTION cont.

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BIOGENIC AMINESBIOGENIC AMINES

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BIOGENIC AMINESBIOGENIC AMINES► NorepinephrineNorepinephrine

Main NT of the sympathetic branch of autonomic nervous Main NT of the sympathetic branch of autonomic nervous systemsystem Binds to Binds to adrenergic receptors (adrenergic receptors ( or or - -many subtypes, many subtypes, 11, , 22, etc), etc) Excitatory or inhibitoryExcitatory or inhibitory depending on receptor type bound depending on receptor type bound Release enhanced by amphetaminesRelease enhanced by amphetamines Removal from synapse blocked by cocaineRemoval from synapse blocked by cocaine

► DopamineDopamine Binds to Binds to dopaminergic dopaminergic receptors of substantia nigra of receptors of substantia nigra of midbrain midbrain and hypothalamusand hypothalamus Release enhanced by amphetaminesRelease enhanced by amphetamines Reuptake block by cocaineReuptake block by cocaine Deficient in Parkinson’s diseaseDeficient in Parkinson’s disease May be involved in pathogenesis of schizophreniaMay be involved in pathogenesis of schizophrenia


Norepinephrine Systems

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Serotonin (5-HT)Serotonin (5-HT)► Synthesized from a.a. Synthesized from a.a. tryptophantryptophan► May play a role in sleep, appetite, and regulation May play a role in sleep, appetite, and regulation of moodsof moods► Drugs that block its uptake relieve anxiety and Drugs that block its uptake relieve anxiety and depressiondepression

SSRI’s = selective serotonin reuptake inhibitorsSSRI’s = selective serotonin reuptake inhibitors Include drugs such as Prozac, Celexa, Lexapro, ZoloftInclude drugs such as Prozac, Celexa, Lexapro, Zoloft


Serotonin

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Gamma Aminobutyric acidGamma Aminobutyric acid(GABA)(GABA)

► Universally inhibitory transmitterUniversally inhibitory transmitter

► Increases influx of Cl- in postsynaptic neuron, hyperpolarising it and thus inhibiting it

► Drugs like benzodiazepines enhance the Drugs like benzodiazepines enhance the ability of GABA to open the ion channel. ability of GABA to open the ion channel.

► There are three types of GABA receptors e.g. There are three types of GABA receptors e.g. GABAGABAA B & C. A B & C.

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GABA receptor binding sitesAzam Basheer

► Include:Include: Substance P – mediator of pain signalsSubstance P – mediator of pain signals Beta endorphin, dynorphin, and enkephalinsBeta endorphin, dynorphin, and enkephalins

► Act as natural opiates, reducing our Act as natural opiates, reducing our perception of painperception of pain Found in higher concentrations in marathoners Found in higher concentrations in marathoners

and women who have just deliveredand women who have just delivered► Bind to the same receptors as opiates and Bind to the same receptors as opiates and

morphinemorphine

Neurotransmitters: PeptidesNeurotransmitters: Peptides

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Glutamic acidGlutamic acid

►The most commonly found The most commonly found neurotransmitter in the brain.neurotransmitter in the brain.

► It is always excitatory. It is always excitatory.

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When glutamate binds to NMDA (N methyl-D-aspartate) receptors, ion channels open allowing Na influx and thus depolarizaing the cell

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ReviewReview


NeurotransmitterNeurotransmitterPostsynaptic Postsynaptic

effecteffectDerived fromDerived from

Site of Site of synthesissynthesis

Postsynaptic Postsynaptic receptorreceptor

FateFate FunctionsFunctions

1.Acetyl choline1.Acetyl choline(Ach)(Ach)

ExcitatoryExcitatory Acetyl co-A +Acetyl co-A +CholineCholine

Cholinergic Cholinergic nerve endingsnerve endingsCholinergic Cholinergic pathways of pathways of brainstembrainstem

1.1.NicotinicNicotinic2.2.MuscarinicMuscarinic

Broken by acetyl Broken by acetyl cholinesterasecholinesterase

Cognitive functions Cognitive functions e.g. memorye.g. memoryPeripheral action e.g. Peripheral action e.g. cardiovascular cardiovascular systemsystem

2. Catecholamines2. Catecholaminesi. Epinephrine i. Epinephrine (adrenaline)(adrenaline)

Excitatory in Excitatory in some but some but inhibitory in inhibitory in otherother

Tyrosine Tyrosine produced in liver produced in liver from from phenylalaninephenylalanine

Adrenal Adrenal medulla and medulla and some CNS some CNS cellscells

Excites both Excites both alpha α &alpha α &beta β beta β receptorsreceptors

1.1.Catabolized to Catabolized to inactive product inactive product through COMT & through COMT & MAO in liverMAO in liver2.2.Reuptake into Reuptake into adrenergic nerve adrenergic nerve endingsendings3.3.Diffusion away Diffusion away from nerve endings from nerve endings to body fluidto body fluid

For details refer For details refer ANS. e.g. fight or ANS. e.g. fight or flight, on heart, flight, on heart, BP, gastrointestinal BP, gastrointestinal activity etc. activity etc. Norepinehrine Norepinehrine controls attention & controls attention & arousal.arousal.

ii.Norepinephrineii.Norepinephrine Excitatory Excitatory Tyrosine, found Tyrosine, found in pons. in pons. Reticular Reticular formation, locus formation, locus coerules, coerules, thalamus, mid-thalamus, mid-brainbrain

Begins inside Begins inside axoplasm of axoplasm of adrenergic adrenergic nerve ending is nerve ending is completed completed inside the inside the secretary secretary vesicles vesicles

αα11 α α22

ββ11 β β22

iii. Dopamineiii. Dopamine Excitatory Excitatory TyrosineTyrosine CNS, CNS, concentrated in concentrated in basal ganglia basal ganglia and dopamine and dopamine pathways e.g. pathways e.g. nigrostriatal, nigrostriatal, mesocorticolimmesocorticolimbic and tubero-bic and tubero-hypophyseal hypophyseal pathwaypathway

DD11 to D to D55

receptorreceptorSame as aboveSame as above Decreased dopamine Decreased dopamine

in parkinson’s in parkinson’s disease.disease.Increased dopamine Increased dopamine concentration causes concentration causes schizophreniaschizophrenia

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effecteffect Derived fromDerived fromSite of Site of

synthesissynthesisPostsynaptic Postsynaptic

receptorreceptorFateFate FunctionsFunctions

3. serotonin3. serotonin(5HT)(5HT)

ExcitatoryExcitatory TryptophanTryptophan CNS, Gut CNS, Gut (chromaffin (chromaffin cells) Platelets cells) Platelets & retina& retina

5-HT5-HT1 1 to 5-HT to 5-HT

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5-HT 5-HT 2 2 A A

receptor mediate receptor mediate platelet platelet aggregation & aggregation & smooth muscle smooth muscle contractioncontraction

Inactivated by MAO Inactivated by MAO to form 5-to form 5-hydroxyindoleacetic hydroxyindoleacetic acid(5-HIAA) in acid(5-HIAA) in pineal body it is pineal body it is converted to converted to melatoninmelatonin

Mood control, sleep, Mood control, sleep, pain feeling, pain feeling, temperature, BP, & temperature, BP, & hormonal activityhormonal activity

4. Histamine4. Histamine ExcitatoryExcitatory HistidineHistidine HypothalamusHypothalamus Three types HThree types H1,1,

HH2 ,2 ,HH3 3 receptors receptors

found in found in peripheral tissues peripheral tissues & the brain& the brain

Enzyme diamine Enzyme diamine oxidase oxidase (histaminase) cause (histaminase) cause breakdownbreakdown

Arousal, pain Arousal, pain threshold, blood threshold, blood pressure, blood flow pressure, blood flow control, gut control, gut secretion, allergic secretion, allergic reaction (involved in reaction (involved in sensation of itch)sensation of itch)

5. Glutamate 5. Glutamate ExcitatoryExcitatory75% of 75% of excitatory excitatory transmission transmission in the brainin the brain

By reductive By reductive amination of amination of Kreb’s cycle Kreb’s cycle intermediate intermediate α –ketoglutarate.α –ketoglutarate.

Brain & spinal Brain & spinal cord e.g. cord e.g. hippocampushippocampus

Ionotropic and Ionotropic and metabotropic metabotropic receptors.receptors.Three types of Three types of ionotropic ionotropic receptors e.g. receptors e.g. NMDA, AMPA NMDA, AMPA and kainate and kainate receptors.receptors.

It is cleared from the It is cleared from the brain ECF by Na brain ECF by Na ++ dependent uptake dependent uptake system in neurons system in neurons and neuroglia.and neuroglia.

Long term Long term potentiation involved potentiation involved in memory and in memory and learning by causing learning by causing CaCa++ ++ influx.influx.

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effecteffect Derived fromDerived fromSite of Site of

synthesissynthesisPostsynaptic Postsynaptic

receptorreceptorFateFate FunctionsFunctions

6. Aspartate6. Aspartate Excitatory Excitatory Acidic aminesAcidic amines Spinal cordSpinal cord Spinal cordSpinal cordAspartate & Glycine form an excitatory / Aspartate & Glycine form an excitatory / inhibitory pair in the ventral spinal cordinhibitory pair in the ventral spinal cord

7. Gama amino 7. Gama amino butyric butyric acid(GABA)acid(GABA)

Major Major inhibitory inhibitory mediatormediator

Decarboxylation Decarboxylation of glutamate by of glutamate by glutamate glutamate decarboxylase decarboxylase (GAD) by (GAD) by GABAergic GABAergic neuron.neuron.

CNSCNS

GABA – A GABA – A increases the Cl increases the Cl -- conductance, conductance, GABA – B is GABA – B is metabotropic metabotropic works with G – works with G – protein GABA protein GABA transaminase transaminase catalyzes. catalyzes. GABA – C GABA – C found found exclusively in exclusively in the retina.the retina.

Metabolized by Metabolized by transamination to transamination to succinate in the citric succinate in the citric acid cycle.acid cycle.

GABA – A causes GABA – A causes hyperpolarization hyperpolarization (inhibition) (inhibition) Anxiolytic drugs like Anxiolytic drugs like benzodiazepine cause benzodiazepine cause increase in Clincrease in Cl-- entry entry into the cell & cause into the cell & cause soothing effects. soothing effects. GABA – B cause GABA – B cause increase conductance increase conductance of Kof K++ into the cell. into the cell.

8. Glycine8. Glycine InhibitoryInhibitory

Is simple amino Is simple amino acid having acid having amino group and amino group and a carboxyl group a carboxyl group attached to a attached to a carbon atomcarbon atom

Spinal cordSpinal cord

Glycine receptor Glycine receptor makes makes postsynaptic postsynaptic membrane more membrane more permeable to Clpermeable to Cl-- ion.ion.

Deactivated in the Deactivated in the synapse by simple synapse by simple process of process of reabsorbtion by active reabsorbtion by active transport back into transport back into the presynaptic the presynaptic membranemembrane

Glycine is inhibitory Glycine is inhibitory transmitted found in transmitted found in the ventral spinal the ventral spinal cord. It is inhibitory cord. It is inhibitory transmitter to transmitter to Renshaw cells.Renshaw cells.

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Formation of serotonin =5-HTHydroxy tryptamineHIAA=hydroxyindoleacetic acid

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Neurotransmission Azam Basheer MD

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