Presentation on theme: "SYNAPSE AND NEUROTRANSMITTER"— Presentation transcript:
1SYNAPSE AND NEUROTRANSMITTER NEUROBIOCHEMISTRYSYNAPSEANDNEUROTRANSMITTERMOHAMMAD HANAFI
2SynapsesA junction that mediates information transfer from one neuron:To another neuronTo an effector cellPresynaptic neuron – conducts impulses toward the synapsePostsynaptic neuron – transmits impulses away from the synapse
3The Synapse Junction between two cells Site where action potentials in one cell cause action potentials in another cellTypes of cells in synapsePresynapticPostsynaptic
5Electrical SynapsesGap junctions that allow local current to flow between adjacent cells. Connexons: protein tubes in cell membrane.Found in cardiac muscle and many types of smooth muscle. Action potential of one cell causes action potential in next cell, almost as if the tissue were one cell.Important where contractile activity among a group of cells important.
6Chemical Synapses Components Presynaptic terminalSynaptic cleftPostsynaptic membraneNeurotransmitters released by action potentials in presynaptic terminalSynaptic vesicles: action potential causes Ca 2+ to enter cell that causes neurotransmitter to be released from vesiclesDiffusion of neurotransmitter across synapsePostsynaptic membrane: when ACh binds to receptor, ligand-gated Na+ channels open. If enough Na+ diffuses into postsynaptic cell, it fires.
7Chemical Synapse Events at a chemical synapse 1. Arrival of nerve impulse opensvolage-gated calcium channels.2. Ca++ influx into presynaptic term.3. Ca++ acts as intracellular messengerstimulating synaptic vesicles to fuse withmembrane and release NT via exocytosis.4. Ca++ removed from terminal bymitochondria or calcium-pumps.5. NT diffuses across synaptic cleft andbinds to receptor on postsynaptic memb6. Receptor changes shape of ion channelopening it and changing membrane potential7. NT is quickly destroyed by enzymes ortaken back up by astrocytes or presynapticmembrane.Note: For each nerve impulse reaching the presynaptic terminal, about 300 vesicles are emptied into the cleft.
8Neurotransmitter Removal Method depends on neurotransmitter/synapse.ACh: acetylcholinesterase splits ACh into acetic acid and choline. Choline recycled within presynaptic neuron.Norepinephrine: recycled within presynaptic neuron or diffuses away from synapse. Enzyme monoamine oxidase (MAO). Absorbed into circulation, broken down in liver.
10Receptor Molecules and Neurotransmitters Neurotransmitter only "fits" in one receptor.Not all cells have receptors.Neurotransmitters are excitatory in some cells and inhibitory in others.Some neurotransmitters (norepinephrine) attach to the presynaptic terminal as well as postsynaptic and then inhibit the release of more neurotransmitter.
11Neurotransmitters found in the nervous system EXCITATORYAcetylcholineAspartateDopamineHistamineNorepinephrineEpinephrineGlutamateSerotoninINHIBITORYGABAGlycine
12NeurotransmittersChemicals used for neuronal communication with the body and the brain50 different neurotransmitters have been identifiedClassified chemically and functionallyChemically:ACh, Biogenic amines, PeptidesFunctionally:Excitatory or inhibitoryDirect/Ionotropic (open ion channels) or Indirect/metabotropic (activate G-proteins) that create a metabolic change in cell
13Chemical Neurotransmitters Acetylcholine (ACh)Biogenic aminesAmino acidsPeptidesNovel messengers: ATP and dissolved gases NO and CO
14Neurotransmitters: Acetylcholine First neurotransmitter identified, and best understoodReleased at the neuromuscular junctionSynthesized and enclosed in synaptic vesiclesDegraded by the enzyme acetylcholinesterase (AChE)Released by:All neurons that stimulate skeletal muscleSome neurons in the autonomic nervous systemBinds to cholinergic receptors known as nicotinic or muscarinic receptorsNicotinic receptorsNeuromuscular junction of skeletal muscles
15Acetylcholine synthesis: In the cholinergic neurons acetylcholine is synthesized from choline. This reaction is activated by cholineacetyltransferaseAs soon as acetylcholine is synthesized, it is stored within synaptic vesicles.
16Structure of AchEAcetylcholinesterase (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.
19Cholinergic Receptors Nicotinic receptors- On neuromuscular junction of skeletal muscle- On all ganglionic neurons of autonomic nervous system- ExcitatoryMuscarinic receptors- All parasympathetic target organs (cardiac and smoothmuscle)- Exciatory in most cases
20AcetylcholineEffects prolonged (leading to tetanic muscle spasms and neural “frying”) by nerve gas and organophosphate insecticides (Malathion).ACH receptors destroyed in myasthenia gravisBinding to receptors inhibited by curare (a muscle paralytic agent-blowdarts in south American tribes) and some snake venoms.
21FUNCTIONS OF ACh Acetylcholine is involved in a variety of functions including pain, recent memory, nicotine addiction, salivation, locomotion, regulation of circadian rhythm and thermoregulation.2. It has also been demonstrated that braincholinergic neurons play a critical role inAlzheimer’s disease, Huntington’s chorea and inthe generation of epileptic seizures.
22Neurotransmitters: Biogenic Amines Include:Catecholamines – dopamine, norepinephrine (NE), and epinephrine (EP)Indolamines – serotonin and histamineBroadly distributed in the brainPlay roles in emotional behaviors and our biological clock
23Synthesis of Catecholamines AA tyrosine parent cpdEnzymes present in the cell determine length of biosynthetic pathwayNorepinephrine and dopamine are synthesized in axonal terminalsEpinephrine is released by the adrenal medulla as a hormoneFigure 11.22
24BIOGENIC AMINES Norepinephrine (aka Noradrenaline) Dopamine Main NT of the sympathetic branch of autonomic nervous systemBinds to adrenergic receptors ( or -many subtypes, 1, 2, etc)Excitatory or inhibitory depending on receptor type bound“Feeling good” NTRelease enhanced by amphetaminesRemoval from synapse blocked by antidepressants and cocaineDopamineBinds to dopaminergic receptors of substantia nigra of midbrain and hypothalamusReuptake block by cocaineDeficient in Parkinson’s diseaseMay be involved in pathogenesis of schizophrenia
25Synthesized from a.a. tryptophan Serotonin (5-HT)Synthesized from a.a. tryptophanThe synthesis of serotonin involve two reactions:1) Hydroxylation:Tryptophan 5- HydroxytryptophanThe enzyme catalyzes this reaction is Tryptophan Hydroxylase.The Co- factor is Tetrahydrobiopterin, which converted in this reaction to Dihydrobiopterin
262) Decarboxylation: 5- hydroxytryptophan Serotonin The enzyme is hydroxytryptophan decarboxylase.Serotonin is synthesized in CNS, & Chromaffin cells.
27Break down of serotonin: Serotonin is degraded in two recations1) Oxidation:5-hydroxytryptoamine + O2 + H2O5- Hydroxyinodole-3-acetaldehyde2) Dehydrogenation5- Hydroxyinodole-3-acetaldehyde hydroxindole-3-acetate (Anion of 5-hydroxyindoleacetic acid)Monoamine oxidaseAldehyde dehydrogenase
28May play a role in sleep, appetite, and regulation of moodsDrugs that block its uptake relieveanxiety and depressionSSRI’s = selective serotonin reuptakeinhibitorsInclude drugs such as Prozac,Celexa, Lexapro, Zoloft
29Neurotransmitters: Amino Acids Include:GABA – Gamma ()-aminobutyric acidGlycineAspartateGlutamateFound only in the CNS
30Amino Acids GABA Main inhibitory neurotransmitter in the brain Inhibitory effects augmented by alcohol and antianxiety drugs like ValiumIncreases influx of Cl- in postsynaptic neuron,hyperpolarising it and thus inhibiting it!GLUTAMATE* Widespread in brain where it represents the majorexcitatory neurotransmitterImportant in learning and memory“Stroke NT” -excessive release produces excitotoxicity:neurons literally stimulated to death; most commonlycaused by ischemia due to stroke (Ouch!)Aids tumor advance when released by gliomas (ouch!)
34FUNCTIONS OF GLUTAMATE 1. Glutamate acts as the major excitatory transmitter inthe brain2. Excess glutamate causes neuronal damage and death,principally by elevating cellular Ca+2. This phenomenonhas significance for a number of pathologies such asAlzheimer’s disease, ALS, Ischemia and Hypoxia,Epilepsy and Schizophrenia.3. Glutamate receptors are involved in a physiologicalphenomenon called long-term potentiation (LTP) - acellular model of learning and memory. The NMDAreceptor activation is an absolute requirement forLTP induction, however, AMPA and metabotropicglutamate receptors also play important roles.
38GABA acts as the major inhibitory transmitter in the brain FUNCTIONS OF GABAGABA acts as the major inhibitory transmitterin the brain2. GABA has been implicated in several neurological andpsychiatricdisorders of humans including Huntington’schorea, epilepsy, alcoholism, Parkinson’s disease andanxiety disorders.3. Antiepileptic and anxiolytic properties ofbenzodiazepine and phenobarbital suggest animportant role of GABA in epilepsy as well asanxiety disorders.
39Neurotransmitters: Peptides Include:Substance P – mediator of pain signalsBeta endorphin, dynorphin, and enkephalinsAct as natural opiates, reducing our perception of painFound in higher concentrations in marathoners and women who have just deliveredBind to the same receptors as opiates and morphine
40Neurotransmitters: Novel Messengers Nitric oxide (NO)A short-lived toxic gas; diffuses through post-synaptic membrane to bind with intracellular receptor (guanynyl cyclase)Is involved in learning and memorySome types of male impotence treated by stimulating NO release (Viagra)Viagra NO release cGMP smooth muscle relaxation increased blood flow erectionCan’t be taken when other pills to dilate coronary b.v. takenCarbon monoxide (CO) is a main regulator of cGMP in the brain
41Summary: Neurotransmitter Molecule Derived From Site of Synthesis AcetylcholineCholineCNS, parasympathetic nervesSerotonin 5-Hydroxytryptamine (5-HT)TryptophanCNS, chromaffin cells of the gut, enteric cellsGABAGlutamateCNSHistamineHistidinehypothalamusEpinephrinesynthesis pathwayTyrosineadrenal medulla, some CNS cellsNorpinephrineCNS, sympathetic nervesDopamineNitric oxide, NOArginineCNS, gastrointestinal tract