Date post: | 07-Aug-2015 |
Category: |
Documents |
Upload: | azam-basheer |
View: | 61 times |
Download: | 2 times |
NeurotransmissionNeurotransmission
Azam Basheer MDAzam Basheer MDHenry Ford NeurosurgeryHenry Ford Neurosurgery
Azam BasheerAzam Basheer
Resting potentialResting potential
Azam Basheer
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.
Azam Basheer
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
Azam Basheer
Ion channelsIon channels
Azam Basheer
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..
Azam Basheer
Action potentialAction potential
► 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.
Azam Basheer
Action potentialAction potential
Azam Basheer
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
Azam Basheer
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
Azam Basheer
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
Azam Basheer
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
Azam Basheer
Types of SynapsesTypes of Synapses
Azam Basheer
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.
Azam Basheer
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
Azam Basheer
Structure of a synapseStructure of a synapse
Azam Basheer
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
Azam Basheer
PresynapticAxon Terminal
PostsynapticMembrane
Terminal Button
Dendritic Spine
Azam Basheer
1. Precursor Transport
Azam Basheer
E
2. Synthesis
Enzymes & cofactors
Azam Basheer
Synapse
Terminal Button Dendritic
Spine
3. StorageIn vesicles
Azam Basheer
Synapse
Ca++
AP
4. Release • via exocytosis• diffusion
Arrival of nerve impulse opens volage-gated calcium channels
Azam Basheer
Structure of the synapseStructure of the synapse
Azam Basheer
Exocytosis: Membrane FusionExocytosis: Membrane Fusion
Ca2+ influx Ca2+ influx 2d 2d messenger Calmodulinmessenger Calmodulin
SNAPs: attachment SNAPs: attachment proteinsproteins
SNAREs: SNAP receptorsSNAREs: SNAP receptors
Azam Basheer
5. Activation NT binds to receptorNT binds to receptor
Azam Basheer
6. Termination
44
1. Diffusion1. Diffusion2. Enzymatic 2. Enzymatic degradationdegradation3. Presynaptic 3. Presynaptic reuptakereuptake
4. 4. AutoreceptorAutoreceptorss
22
3322
11
11Azam Basheer
ReceptorsReceptors
• neurotransmitter specific postsynaptic receptors
• open to allow ions to flow into the postsynaptic neuron
• two main types•ionotropic•metabotropic
Azam Basheer
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)
Azam Basheer
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
Azam Basheer
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.
Azam Basheer
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
Azam Basheer
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))
Azam Basheer
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- -
Azam Basheer
NeurotransmittersNeurotransmitters
Azam BasheerAzam Basheer
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
Azam Basheer
► First neurotransmitter identifiedFirst neurotransmitter identified► Synthesized and enclosed in synaptic Synthesized and enclosed in synaptic
vesiclesvesicles
► DegradationDegradation
AcetylcholineAcetylcholine
Acetylcholine Choline + Acetate
Acetylcholine Esterase (AchE)
Azam Basheer
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
Azam Basheer
Where it is FoundWhere it is Found
Azam Basheer
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
Azam Basheer
Azam Basheer
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
Azam Basheer
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.
Azam Basheer
BIOGENIC AMINESBIOGENIC AMINES
Azam Basheer
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
Azam BasheerAzam Basheer
Norepinephrine Systems
Azam Basheer
Azam Basheer
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
Azam BasheerAzam Basheer
Serotonin
Azam Basheer
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.
Azam Basheer
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
Azam Basheer
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.
Azam Basheer
When glutamate binds to NMDA (N methyl-D-aspartate) receptors, ion channels open allowing Na influx and thus depolarizaing the cell
Azam Basheer
ReviewReview
Azam BasheerAzam Basheer
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
Azam Basheer
NeurotransmitterNeurotransmitterPostsynaptic Postsynaptic
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
77
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.
Azam Basheer
NeurotransmitterNeurotransmitterPostsynaptic Postsynaptic
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.
Azam Basheer
Azam Basheer
Azam Basheer
Azam Basheer
Formation of serotonin =5-HTHydroxy tryptamineHIAA=hydroxyindoleacetic acid
Azam Basheer
Azam Basheer