1Overview of the Autonomic Nervous SystemRichard D. YeProfessor of PharmacologyCollege of MedicineTel. 996-5087Room 4143, COMRBE-mail: [email protected] nervous systemSomatic nervous system(non-autonomic, voluntary)Skeletal muscleAutonomic nervous system(vegetative, visceral, involuntary;enteric nervous system)Heart, blood vessels,glands, other visceralorgans, smooth muscleThe Peripheral Nervous SystemSomatic and visceral afferent nervesAnatomic classification: sympathetic (fight or flight)parasympathetic (rest and digest)Neurotransmitter-based classification: adrenergic, cholinergic, dopaminergic.2What are the major neurotransmitters in the PNS?How are they synthesized? What are the rate-limiting steps?What are the regulatory mechanisms for neurotransmitter synthesis?How are neurotransmitters removed after release?Students are expected to learn through these two lectures:What are the major sites of drug action in the PNS?How receptors respond to adrenergic / cholinergic agonists andantagonists? • He discovered that stimulation of the vagus of a frog heart causes release of a substance that, when transferred to a second heart, could slow heart rate. He called this “Vagusstoff”, demonstrating the chemical basis of neurotransmission.Otto Loewi (Nobel Laureate, 1936)• He also found that atropine can prevent the inhibitory action, but not the release of the “Vagusstoff”.• Incubation of the “Vagusstoff” with frog heart homogenate inactivates it.• Physostigmine enhances the effect of vagus stimulation on the heart, and prevents the destruction of “Vagusstoff”.3On mature consideration, in the cold light of the morning, I would not have done it. After all, it was an unlikely enough assumption that the vagus should secrete an inhibitory substance; it was still more unlikely that a chemical substance that was supposed to be effective at very close range between nerve terminal and muscle be secreted in such large amounts that it would spill over and, after being diluted by the perfusion fluid, still be able to inhibit another heart. (Loewi 1921) ElectricalStimulation(impulse)Chemical(neurotransmitter)Neurotransmitter:A chemical that transmits signals from one neuron to anotheror from a neuron to an effector cell. Chemical(intracellularmessengers)Electrical(membraneion channels)Physiologicalfunctions4Pre-synapticnerve cellPost-synapticnerve cellSynapticcleftCa2+Na+Precursors(choline/tyrosine)Definition of synapse:A junctional connection between two neurons, across which a signal can passPrecursorNeurotransmitterStorageReleaseRecognitionby receptorsMetabolicdispositionPre-synaptic neuron: Where a neurotransmitter is synthesized, stored and released upon cell activation. Post-synaptic neuron or effector cell: Where neurotransmitter is detected and its action translated into cellular activities. ThoracolumbarCranialSacralCNS Pre-ganglionic Ganglion Post-ganglionicParasympatheticAchNicotinicAchNicotinicAchNicotinicAchNicotinicAchNicotinicEpiSympatheticSympatheticSympatheticSympathetic (adrenal medulla)Motor (somatic)AchAchMuscarinicMuscarinicNEAdrenergic(α, β)DDopaminergic(D1)AchNicotinicCardiac & smoothmuscles, gland cells,nerve terminalsCardiac & smoothmuscles, gland cells,nerve terminalsSweat glandsRenal vascularsmooth muscleReleased intobloodSkeletal muscleAch = acetylcholine NE = norepinephrineEpi = epinephrineD = dopamineEffectors5• All preganglionic and parasympathetic postganglionic neurons use acetylcholine as neurotransmitter. Ach is the neurotransmitter at ganglia, nmj, and muscarinic tissue synapses.• Most postganglionic sympathetic neurons use norepinephrine which is an adrenergic neurotransmitter.Pharmacological division of cholinergic vs. adrenergicneurotransmission• There are exceptions: Cholinergic transmission in sympathetic system –all ganglia, adrenal medulla, sweat glads (muscarinic). Dopaminergicinnervation in sympathetic system – renal blood vessels.Synthesis & StorageActionpotentialMetabolismRecognition(action)Key Steps in Neurotransmission:Strategies for Pharmacological Intervention:Block synthesis and storage: Usually rate-limiting steps; produce long-term effectsBlock release: Rapid action and effectiveInterfere with metabolism: Can be reversible or irreversible; blocking metabolism increases effective neurotransmitter concentrationsInterfere with action: Receptor antagonists & agonists; high specificityRelease6Synthesis of acetylcholine:CH3CH3CH3N+–CH2–CH2–OHCoA–S–C–CH3OCholineAcetyl-CoA+CholineacetyltransferaseCH3CH3CH3N+–CH2–CH2–O–C–CH3OCoA-SH+CoAAcetylcholineSynthesis, storage and release of acetylcholine:Pre-synapticcellPost-synapticcellAchCa2+Na+Choline(10 µM)CholineRecognitionby receptorsCa2+AchAchAchNerveimpulseNNNMAchAc-CoAChATAchAchEAchEcholine+ acetic acidCAT = choline acetyltransferaseAchE = acetylcholinesteraseSynapticcleftAntiporter7CH3COOH+AchE(CH3)3N+–CH2–CH2–OH(CH3)3N+–CH2–CH2–O–C–CH3OH2O(-) (H)AchETrp-86Glu-334His-447Ser-203Degradation of acetylcholine:Steps involved in the action of acetylcholinesterase:1. Binding of substrate (Ach)2. Formation of a transient intermediate (involving -OH on Serine 203, etc.)3. Loss of choline and formation of acetylated enzyme4. Deacylation of AchE (regeneration of enzyme)600,000 Ach molecules / AchE / min= turnover time of 150 microsecondsCholine Acetic acidHOHOCH2NHCH3OHCHEpinephrineHOHOCH2NH2OHCHNorepinephrineHOHOCH2NH2CH2DopamineHOHOHCNH2CH2DOPACOOHHOHCNH2CH2TyrosineCOOHTHDD (L-AAD)DBHPNMTAdrenal medullaSynthesis of CatecholaminesTyrosine hydroxylaseDopa decarboxylase(L-amino aciddecarboxylase)Dopamine β-hydroxylasePhenylethanolamine-N-methyl transferase13Julius Axelrod (Nobel Laureate, 1970)His discoveries concern the mechanisms which regulate the formation of norepinephrinein the nerve cells and the mechanisms which are involved in the inactivation of this important neurotransmitter.8Pre-synapticPost-synapticCa2+Na+TyrosineCellular messengersand effectsDiffusion, metabolismTyrosineDopaTHDDDopamine(DA)NEDBHATPCa2+NEDBHATPNENECOMTαRβRα2RNE(-)SignalRegulation of Norepinephrine Synthesis and Metabolism:Uptake-1Normetanephrine (NMN)Degradation of Catecholamines:HOHOCH2NHCH3OHCHEpinephrineHOHOCH2NH2OHCHNorepinephrineHOHOCH2NH2CH2DopamineHOHOCOOHOHCHDihydroxymandelic acid(DOMA)HOCH3OCOOHOHCH3-Methoxy-4-hydroxy-mandelic