Presentation on theme: "Academic Half-Day The Chemical Basis for Neuronal Communication"— Presentation transcript:
1 Academic Half-Day The Chemical Basis for Neuronal Communication Marie-Pierre Thibeault-Eybalin, R4November 5th, 2008
2 Introduction 100 billion (1011) neurons in the brain Up to 100,000 terminal contacts / neuron1016 connections between neurons / brainConnections = SynapsesChemical messenger is released at pre-synaptic membrane of axon or dendrite terminalIt travels across synaptic cleftIt binds onto its receptor on post-synaptic membrane of other neuronIt activates effector systemChemical messenger may be released at non-synaptic locations to influence distant neurons
3 Criteria to define chemical messenger as neurotransmitter Localization: A putative neurotransmitter must be localized to the presynaptic elements of an identified synapse and must be present also within the neuron from which the presynaptic terminal arises.Release: The substance must be shown to be released from the presynaptic element upon activation of that terminal and simultaneously with depolarization of the parent neuron.Identity: Application of the putative neurotransmitter to the target cells must be shown to produce the same effects as those produced by stimulation of the neurons in question.
5 Synaptic transmission Variable synaptic delay from pre-synaptic neurotransmitter release to excitation or inhibition of post-synaptic neuronSynaptic delay depends on complexity of transduction mechanisms at post-synaptic membraneSynaptic delayReceptorNeurotransmitterEffector systemFastFew msecLigand-gated ion channelSmall moleculeFlux of ions to generate transmembrane electrical potential (EPSP, IPSP ± AP if reach threshold)SlowHundreds of msecG-protein-coupledNeuropeptideIndirect effect on ion channelEnzyme activation to produce 2nd chemical messenger (intracellular)
7 Regulatory mechanisms To regulate amount of neurotransmitter releasePre-synaptic receptor-mediated autoregulationNeurotransmitter in synaptic cleft binds to pre-synaptic receptorInhibitory feedback mechanismRetrograde transmission2nd chemical messenger diffuses from post-synaptic to pre-synaptic membranes, e.g. NO
8 Secretory vesicles Small = Synaptic vesicles For small moleculesSynthesized within vesicles, e.g. NE or uploaded by high-affinity ATP-proton-coupled transporters in terminals, e.g. AChRecycled50 nm diameterCluster in active zonesLarge dense-cored vesiclesFor neuropeptides, "built-in" in neuronal soma ± co-stored small moleculeNot-recyclednm diameterFound in intraneuronal locations + terminals, less numerousNeurosecretory vesiclesHypothalamic neuron terminals in neurohypophysisFor neurohormonesnm diameter
11 Signal transduction Most receptors are transmembrane glycoproteins Binding of neurotransmitter to receptor induces conformational change4 transduction mechanismsLigand-gated ion channelsG-protein-coupled receptorsEnzymes e.g. tyrosine kinaseLigand-dependent regulators of nuclear transcription e.g. testosteroneReceptors often named after family of neurotransmitters they bind e.g. cholinergic and adrenergic receptorsMultiple subtypes based on responseNicotinic ACh receptors usually excitatoryMuscarinic ACh receptors usually inhibitoryIndividual neurotransmitter family members of have different potencyRank order of potency according to EC50%Concentration of individual neurotransmitter required to reach 50% of maximal response expectedThe same neurotransmitter may have excitatory or inhibitory responses depending on receptor type
12 Structure of neurotransmitter receptors Ligand-gated ion channelsMultiple subunits = transmembrane glycoproteins connected via intra-and extra-cellular loopsCylindricalBinding site in transmembrane portionConformation changes opens gate inside channelSelectively pass small ions2 genetic families based on AA sequence homologyNicotinic ACh, serotonin, GABA, glycineGlutamate
13 G-protein-coupled receptors Glycoprotein chains with multiple transmembrane loops-helicesβ-pleated sheetsBinding site in transmembrane or extra-cellular portion3 componentsReceptorGTP-binding heterotrimerEffector protein (enzyme or ion channel)ExamplesRhodopsinOdorantsBiogenic aminesBioactive peptidesβ2-adrenergic receptor
15 Examples of effector proteins Enzyme2nd intracellular messengerAdenylyl cyclasecAMPGuanylate cyclasecGMPPhospholipase CIP3 and DAGPhospholipase A2Members of the eicosanoid family
16 Receptor regulation Desensitization Reduction in receptor agonist-induced response after seconds to minutes of stimulation mediated by conformational changesHomologousHeterologousPhosphorylation of intracellular portion of receptor altering its binding affinityDownregulation of receptor number at post-synaptic membraneInternalization of receptor by invagination of post-synaptic membrane
17 Maintenance of synaptic environment To reduce or eliminate neurotransmitters in synaptic cleftEnzymatic degradationACh cleaved by acetylcholinesteraseNeuropeptides degraded by peptidasesTransporter-mediated reuptake of small molecules (not neuropeptides) by pre-and post-synaptic neuron or glia (extraneuronal monoamine transport; EMT)NET for norepinephrineDAT for dopamineSERT for serotoninAfter reuptake, neurotrasmitter either recycled or degraded by mitochondria (MAO)COMT for norepinephrine
18 Pharmacologic modification of synaptic transmission Drugs may affect:Neurotransmitter synthesisVesicular uptake and storageDepolarization-induced exocytosisNeurotransmitter receptor bindingTermination of neurotransmitter actionPost-synaptic effector system
20 Synopsis of clinical points Many drugs function by altering chemical transmission at the synaptic cleft.Neuropeptides play a role in the body's response to stress.Some drugs must traverse the plasma membrane to access receptors.Epinephrine is used in cardiopulmonary resuscitation and to treat anaphylactic reactions.The excess production of catecholamines, seen in tumors such as pheochromocytoma, can be treated by the drug metyrosine.Reserpine is sometimes used to treat hypertension.Reserpine may precipitate Parkinson-like symptoms or galactorrhea, or worsen clinical depression.α-Methyldopa is effective for managing hypertension during pregnancy.The side effects of guanethidine include reduced heart rate, nasal congestion, and orthostatic hypotension.Propranolol is used in the management of angina pectoris, hypertension, and congestive heart failure.Yohimbine may be effective in treating male impotence of vascular or psychogenic origin.Amphetamines enhance motor performance and relieve fatigue; these are habit-forming if used inappropriately.