003 biokimia saraf

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  • Neuro biochemistryDr. SarYOno, SKp.,MKes. Medical biochemistry unit

  • Neuron Communication by neurons is based on changes in the membranes permeability to ions.A typical neuron has a dendritic region and an axonal region.The dendritic region is specialized to receive information, typically neurotransmitters; it then undergoes graded potentials.The axonal region is specialized to deliver information: after undergoing action potentials, neurotransmitters are released from the axon terminal.

  • Synapses An interneuronal junctionsTwo kinds of synapsesChemical synapsesElectric synapses

  • Chemical SynapsesVesicles contain neurotransmitters that can alter the ionic conductivity of the postsynaptic membraneThe postsynaptic membrane is separated from the presynaptic membrane by a synaptic cleft having a width of 20 nmAn increase in sodium ion/Na+, permeability tends to depolarize the postsynaptic membrane (excitatory)An increase in potassium ion, permeability hyperpolarizes the membrane (inhibitory)

  • Chemical vs. Electric SynapseElectrical synapse Impulses can be regenerated without interruption in adjacent cells Gap junctions Adjacent cells electrically coupled through a channel Each gap junction is composed of 12 connexin proteins Examples Smooth and cardiac muscles, brain, and glial cells

    Chemical synapse Terminal bouton is separated from postsynaptic cell by synaptic cleft NTs are released from synaptic vesicles Vesicles fuse with axon membrane and NT released by exocytosis Amount of NTs released depends upon frequency of APExamples: otot lurik/rangka

  • Chemical vs. Electric SynapseChemical Synapse Unidirectional Current Flow Limited By Neurotransmitter Diffusion Nonlinear

    Electric Synapse Bidirectional Very Fast Current Flow Linear

  • Ion gating in axonChanges in membrane potential caused by ion flow through ion channelsVoltage gated (VG) channels open in response to change in membrane potentialGated channels are part of proteins that comprise the channelCan be open or closed in response to change2 types of channels for K+1 always open1 closed in resting cellChannel for Na+Always closed in resting cellsSome Na+ does leak into the cells

  • How A Nerve Cell FiresNerve cell membrane is a lipid bilayer with embedded proteins.ATP-powered ion pumps keep outside of membrane + charged, inside charged.Channels in membrane can let + ions pass through. Channels normally closed.Neurotransmitter gated channels collapse (depolarize) voltage gradient.Voltage gated channels propagate depolarization in a wave down axon.

  • Action potentialsStimulus causes depolarization to thresholdVoltage gated (VG) Na+ channels openElectrochemical gradient inward+ feedback loopRapid reversal in membrane potential from 70 to + 30 mVVG Na+ channels become inactivated

    VG K+ channels openElectrochemical gradient outward-feedback loop

  • Action potentialsDepolarization and repolarization occur via diffusion, do not require active transportOnce AP completed, Na+/K+ ATPase pump extrudes Na+, and recovers K+All or noneWhen threshold reached, maximum potential change occursAmplitude does not normally become more positive than + 30 mV because VG Na+ channels close quickly and VG K+ channels openDuration is the same, only open for a fixed period of timeCoding for Stimulus IntensityIncreased frequency of AP indicates greater stimulus strengthRecruitmentStronger stimuli can activate more axons with a higher threshold

  • (Potensial berjenjang)

  • Synaptic transmissionNT release is rapid because many vesicles form fusion complexes at docking siteAP travels down axon to boutonVG Ca2+ channels open Ca2+ enters bouton down concentration gradient Inward diffusion triggers rapid fusion of synaptic vesicles and release of NTsCa2+ activates calmodulin, which activates protein kinaseProtein kinase phosphorylates synapsins Synapsins aid in the fusion of synaptic vesicles

  • Inhibit transmiter releaseInhibit transmiter uptake

  • organofosfat

  • The Dopamine HypothesisF. I. Carroll et al, Journal of Medical Chemistry 42, 2721-36 (1999)

  • Synapses are major targets of neuroactive drugsCocaineXAdenosineCaffeineXNicotineCaffeine: inhibits adenosine receptorsNicotine: activates acetylcholine receptorsCocaine: inhibits uptake of DA, NE, 5HTEthanol?AChReceptor

  • Synapses are the targets of therapeutic drugs

    Synapses are also the sites of actions of many classes of therapeutic drugs which act upon the brain.1) Antidepressant drugs generally act by inhibiting the uptake of serotonin and norepinephrine2) An important class of analgesic drugs, the opiate analgesics, activate receptors for neurotransmitters known as the endorphins and enkephalins 3) Antipsychotic drugs block or inhibit receptors for dopamine4) Some types of anticonvulsant drugs potentiate the effects of the neurotransmitter GABA

    Antidepressant drugs: serotonin uptake inhibitors Analgesics (morphine): opiate receptor agonists Antipsychotic drugs: DA receptor antagonistsAnticonvulsant drugs; GABA, modulatorsAntianxiety agents: GABA, modulators

  • Zigmond et al (1999) Fig 8.3

    Stages 1 & 2Accumulation of a precursor amino acid into the neuron which is metabolized to yield the mature transmitter (ZZ)Stage 3Transmitter is then accumulated into vesicles by the vesicular transporter for storage and release. Stages 4 & 5Transmitter is released into synaptic cleft to interact with post-synaptic receptors or autoreceptors that regulate transmitter release, synthesis or firing rate.Stage 6 9Inactivation and termination of the action of the released transmitter by reuptake through neuronal transporter proteins, enzymatic degradation, uptake by glial cells or passive diffusion

    LIFE CYCLE OF A TRANSMITTER

  • Neurotransmiter (bekerja cepat)Klas I ; asetilkolinKlas II (amina); norepinefrin, epinefrin, dopamin, serotonin, histaminKlas III (asam amino); GABA, glisin, glutamat, aspartatKlas IV; NO

  • Neuropeptida (bekerja lambat) Releasing hormonPeptida hipofise; LH, GH, endorfin, prolaktin, oksitosin dllPeptida usus dan otak; enkefalin, substansi P, gastrin, insulin, glukagon dllDari jaringan lain; angiotensin, bradikinin, kalsitonin dll

  • Neurotransmiter vs neuropeptidaBekerja cepatMolekul kecilDisintesis di sitosolTempat kerja di membran pasca sinapBekerja lambatMolekul besarDisintesis di ribosom, retikulum endoplasma, aparatus golgiTempat non sinaps, di sel prasinaps maupun pasca sinaps

  • Letak neurotransmiter pentingAsetilkolin-disekresi di sebagian besar otak, otot rangka dllNorepinefrin- disekresi di neuron yang badan selnya di batang otak dan hipotalamusDopamin di substansia nigraGABA- di medula spinalis, serebelum, ganglia basalis, sebagian korteksSerotonin- di rafe medial batang otakGlutamat di presinap sensorik korteks

  • Neurotransmitter in the CNS There is a broad set of different neurotransmitters in the CNSNeurotransmitters can be activating or inhibitoryNeurotransmitter bind to specific receptors and cause excitatory post synaptic potential (EPSP) or inhibitory post synaptic potentials (IPSP) Activating transmitter act by opening kation-channels (Na+,K+, Ca2+)Inhibitory transmitter act by opening anion (mainly Cl- -Channels)Important neurotransmitter:Acetylcholine (Transmitter of Neuro-muscular junctions)DopamineSerotoninGlycin (inhibitory)AspartateGlutamateGABA (g-amino-butyric acid, inhibitory)Adrenaline/Noradrenaline (Autonomous nervous system)

  • NeurotransmittersGlutamateg-AminobutyrateSerotoninTyrosineTryptophanAmino AcidPrecursorsPLP:piridoksal fosfat

  • PathwayDopamineNorepinephrineSerotonin(5-HT)TyrosineTryptophanCatecholaminesDOPA5HTPTHBP: tetrahydrobiopterin

  • Acetylcholine+ cholineAcetyl-CoACholine acetyltransferaseAcetylcholinesterase

  • Catecholamine BiosynthesisTyr hydroxylaseO2TyrosineDihydroxyphenylalanine (DOPA)DopamineDOPAdecarboxylaseCO2DopaminehydroxylaseNorepinephrineCatecholEpinephrine(Adrenaline)SAMS-Adenosyl-homocysteineMethyl transferaseDOPA, dopamine, norepinephrine,and epinephrine are all neurotransmitters

  • L-DOPA in ParkinsonismBlood BrainBloodBrain BarrierL-DOPAL-DOPA DopamineDopamineCarbidopaBlocksParkinsonism associated with dopamine in brain through loss ofneurons in basal ganglia.Carbidopa + L-DOPA

  • Monoamine Oxidase (MAO)MAO(in mitochondria)R ROH H NorepiOH CH3 EpiH H DopamineUrinary metaboliteMAO inhibitors (e.g., tranylcypromine) are useful in the treatment of depression Brain levels of dopamine and norepi.; also serotonin

    AldehydedehydrogenaseR=OH Vanillylmandelic acid (VMA)R=H Homovanillic acid (HVA)

  • Catechol-O-Methyl Transferase (COMT)COMTInactive metaboliteSAMS-Adenosyl-homocysteine COMT found in cytoplasm Terminates activity of catecholamines Catecholamine excretion products result from combined actions of MAO and COMT Inhibitors of COMT (e.g., tolcapone) useful in Parkinsons diseaseActive catecholamine

  • Tryptophan Metabolism: Serotonin FormationTryptophan(Trp)Indole ringTrphydroxylaseO25-Hydroxy-tryptophanDecarboxylaseCO25-Hydroxy-tryptamine (5-HT);Serotonin

  • Serotonin Serotonin formed in: Brain (neurotransmitter; regulation of sleep, mood, appetite) Platelets (platelet aggregation, vasoconstriction) Smooth muscle (contraction) Gastrointestinal tract (enterochromaffin cells - major storage site)

    Drugs affecting serotonin actions used to treat: DepressionSerotonin-selective reuptake inhibitors (SSRI) Migraine Schizophrenia Obsessive-compulsive disorders Chemotherapy-induced emesis

    Some hallucinogens (e.g., LSD) act as serot