4Neurotransmitters Properties Synthesized in the presynaptic neuron Localized to vesicles in the presynapticneuron Released from the presynaptic neuronunder physiological conditions Rabidly removed from the synaptic cleft byuptake or degradation Presence of receptor on the post-synapticneuron Binding to the receptor elicits a biologicalresponseR.E.B, 4MedStudents.com, 2003
10Fate of neurotransmitters Are as ,1. It is consumed ( broken down or usedup) at postsynaptic membrane leadingto action potential generation.2. Degraded by enzymes present insynaptic cleft.3. Reuptake mechanism( reutilization)this is the most common fate.
11Types of responses onpostsynaptic membrane Excitatory postsynaptic potential(EPSPs)It is caused by depolarization. Inhibitory Postsynaptic potential (IPSPs)It is caused by hyperpolarization.
12Fast & Slow Postsynapticpotentials Fast EPSPs & IPSPs work throughligand gated ion channels.eg. Nicotinicreceptors(at the level of neuromuscularjunction) Slow EPSPs & IPSPs are produced bymulti step process involving G proteineg. Muscarinic receptors ( at the level ofautonomic gangila)
13EPSPExcitatory PostsynapticPotentialMembrane depolarizesResult from opening of chemically gated cation channelsAllow Na+, K+, Ca++ to pass into the neuronNa+ in flow is greater than Ca++ inflow or K+ outflowElectrical and concentration gradients promote inflow
14IPSPInhibitory Postsynaptic PotentialMembrane hyperpolarizesIncreases membrane potential by making inside more negativeGeneration of nerve impulse more difficultOften result from opening chemically gated Cl- or K+ channelsside becomes more negative by Cl- inflow or increased K+ outflo
15Acetylcholine synthesis: In the cholinergic neurons acetylcholine issynthesized from choline. This reaction isactivated by cholineacetyltransferaseAs soon as acetylcholine is synthesized,it is stored within synaptic vesicles.
16Release of acetylcholine frompresynaptic neurons: 1)When the nerve impulse (Action potential) moves down the presynapticaxon to the terminal bulb the change in the membrane action potentialcauses 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.
17Binding of acetylcholine to thepostsynaptic receptors: The postsynaptic membrane of the receptor dendrite has specific cholinergicreceptors toward which the neurotransmitter diffuses. Binding ofacetylcholine trigger the opening of ion channels in the postsynapticmembrane initiating action potential that can pass in the next axon Acetylcholine receptors are ion channels receptorsmade of many subunits arranged in the form [(α2)(β)(γ)(δ)] Binding of two acetylcholine molecules to thereceptors will rotate the subunits in which the smallerpolar residues will line the ion channel causing theinflux of Na+ into the cell and efflux of K+ resulting ina depolarization of the postsynaptic neuron and theinitiation of new action potential
18Removal of Acetylcholine from the synapticcleft: In order to ready the synapse for another impulses: 1) The neurotransmitters, which are released from the synaptic vesicles, arehydrolyzed 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 terminalbulb by endocytosis, must be filled with acetylecholine.AcetylcholinestraseAcetylcholinestrase
19Structure of AchE Acetylcholinesterase (AchE) is an enzyme,which hydrolyses the neurotransmitteracetylcholine. The active site of AChE ismade up of two subsites, both of which arecritical to the breakdown of ACh. Theanionic site serves to bind a molecule ofACh to the enzyme. Once the ACh isbound, the hydrolytic reaction occurs at asecond region of the active site called theesteratic subsite. Here, the ester bond ofACh is broken, releasing acetate andcholine. Choline is then immediately takenup again by the high affinity choline uptakesystem on the presynaptic membrane.
20Catecholamine Synthesis (Dopamine,Norepinephrine and Epinephrine). 1) First Step: Hydroxylation: In this step: the reaction involves the conversion of tyrosine, oxygenand tetrahydrobiopterin to dopa & dihydrobiopterin. Thisreaction is catalyzed by the enzyme tyrosine hydroxylase. It isirreversible reaction. 2) Second step: Decarboxylation: In this step: the dopa decaboxylase will catalyze the decaoxylation ofdopa to produce dopamine. The deficiency of this enzyme cancause Parkinson’s disease. It is irreversible reaction. The cofactor inthis reaction is the PLP (pyridoxal phosphate). In the nerve cells thatsecrete dopamine as neurotransmitter the pathway ends at this step.
213) Third step: Hydroxylation:This reaction is catalyzed by the enzyme dopamine β- hydroxylase.The reactants include dopamine, O2and ascorbate (vitamin C).The products are norepinephrine, water and dehydroascorbate. Itis an irreversible reaction). The end product in noradrenergiccells 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).
23Serotonin 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 toDihydrobiopterin.2) 2) Decarboxylation:5- hydroxytryptophan SerotoninThe enzyme is hydroxytryptophan decarboxylase.•Serotonin is synthesized in CNS, & Chromaffin cells.
25Break down of serotonin: Serotonin is degraded in two reactions1) Oxidation:1) Oxidation:5-hydroxytryptoamine + O2 + H2O 5- Hydroxyinodole-3-acetaldehyde2) Dehydrogenation2) Dehydrogenation5- Hydroxyinodole-3-acetaldehyde 5-hydroxindole-3-acetate(Anion of 5-hydroxyindoleacetic acid)Monoamine oxidaseAldehyde dehydrogenase
27NeurotransmitterPostsynapticeffectDerived fromSite ofsynthesisPostsynapticreceptorFate Functions3. serotonin(5HT)Excitatory Tryptophan CNS, Gut(chromaffincells) Platelets& retina5-HT1to 5-HT75-HT 2Areceptor mediateplateletaggregation &smooth musclecontractionInactivated by MAOto form 5-hydroxyindoleaceticacid(5-HIAA) inpineal body it isconverted tomelatoninMood control, sleep,pain feeling,temperature, BP, &hormonal activity4. Histamine Excitatory Histidine Hypothalamus Three types H1,H2 ,H3receptorsfound inperipheral tissues& the brainEnzyme diamineoxidase(histaminase) causebreakdownArousal, painthreshold, bloodpressure, blood flowcontrol, gutsecretion, allergicreaction (involved insensation of itch)5. Glutamate Excitatory75% ofexcitatorytransmissionin the brainBy reductiveamination ofKreb’s cycleintermediateα –ketoglutarate.Brain & spinalcord e.g.hippocampusIonotropic andmetabotropicreceptors.Three types ofionotropicreceptors e.g.NMDA, AMPAand kainatereceptors.It is cleared from thebrain ECF by Na +dependent uptakesystem in neuronsand neuroglia.Long termpotentiation involvedin memory andlearning by causingCa++influx.
28NeurotransmitterPostsynapticeffectDerived fromSite ofsynthesisPostsynapticreceptorFate Functions6. Aspartate Excitatory Acidic amines Spinal cord Spinal cordAspartate & Glycine form an excitatory /inhibitory pair in the ventral spinal cord7. Gama aminobutyricacid(GABA)MajorinhibitorymediatorDecarboxylationof glutamate byglutamatedecarboxylase(GAD) byGABAergicneuron.CNSGABA – Aincreases the Cl -conductance,GABA – B ismetabotropicworks with G –protein GABAtransaminasecatalyzes.GABA – Cfoundexclusively inthe retina.Metabolized bytransamination tosuccinate in the citricacid cycle.GABA – A causeshyperpolarization(inhibition)Anxiolytic drugs likebenzodiazepine causeincrease in Cl-entryinto the cell & causesoothing effects.GABA – B causeincrease conductanceof K+into the cell.8. Glycine InhibitoryIs simple aminoacid havingamino group anda carboxyl groupattached to acarbon atomSpinal cordGlycine receptormakespostsynapticmembrane morepermeable to Cl-ion.Deactivated in thesynapse by simpleprocess ofreabsorbtion by activetransport back intothe presynapticmembraneGlycine is inhibitorytransmitted found inthe ventral spinalcord. It is inhibitorytransmitter toRenshaw cells.
29RECEPTORSDYSFUNCTION1. Presynaptic effecti) Botulinum toxin: Its an exotoxin thatbinds to the presynaptic membraneand prevents the release of Achresulting in weakness and reduction oftone. It is used to control dystonia inwhich body shows overactivemuscular activity.
30ii) Lumbert – Eaton syndromeAntibodies directed against Ca++channelslocated in presynaptic terminals andinterfere with transmitter release causingweakness.iii)NeuromyotoniaPatient complains of muscle spasm andstiffness resulting in continuous motoractivity in the muscle. It is cased byantibody directed against the presynapticvoltage gated K+channel so that the nerveterminal is always in a state ofdepolarization
312. Effects at Postsynaptic level:i) Curare binds to the acetylcholinereceptor (AchR) and prevents Ach fromacting on it and so that it inducesparalysis.ii) Myasthenia gravis: is caused by anantibody against the Ach receptors andAch receptors are reduced hence theAch released has few Ach receptoravailable to work and patients complainof weakness that increases withexercise.
32INTRACELLULAR SIGNAL TRANSDUCTION OFSYNAPTIC NEUROTRANSMISSIONhttp://sites.sinauer.com/neuroscience5e/animations07.01.htmlhttp://sites.sinauer.com/neuroscience5e/animations07.02.html