1Overview: Pharmacology of thePeripheral Nervous SystemRichard D. YeProfessor of PharmacologyCollege of MedicineTel. 996-5087Room 4143, COMRBE-mail: [email protected] IPNS transmitter metabolismPart IIPNS receptor functionEfferent 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, can have inhibitory effect. He called this “Vagusstoff”.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”.3ElectricalStimulation(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)PhysiologicalfunctionsPre-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.4ThoracolumbarCranialSacralCNS 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 = dopamineEffectorsSynthesis & StorageActionpotentialReleaseMetabolismActionKey Steps in Neurotransmission:Strategies for Pharmacological Intervention:Blocking synthesis and storage: Usually rate-limiting steps; produce long-term effectsBlocking release: Rapid action and effectiveInterfere with metabolism: Can be reversible or irreversible; blocking metabolism increases effective neurotransmitter concentrationsInterfere with action: Receptor antagonists & agonists; high specificity5Synthesis, storage and release of acetylcholine:CoA-SH(CH3)3N+–CH2–CH2–OH CoA–S–C–CH3O+(CH3)3N+–CH2–CH2–O–C–CH3O+CATPre-synapticcellPost-synapticcellAchCa2+Na+Choline(10 µM)CholineRecognitionby receptorsCa2+AchAchAchNerveimpulseNNNMAchAc-CoAChATAchAchEAchEcholine+ acetic acidCAT = choline acetyltransferaseAchE = acetylcholinesteraseSynapticcleftAntiporterCH3COOH+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 acid6HOHOCH2NHCH3OHCHEpinephrineHOHOCH2NH2OHCHNorepinephrineHOHOCH2NH2CH2DopamineHOHOHCNH2CH2DOPACOOHHOHCNH2CH2TyrosineCOOHTHDD (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.Pre-synapticPost-synapticCa2+Na+TyrosineCellular messengersand effectsDiffusion, metabolismTyrosineDopaTHDDDopamine(DA)NEDBHATPCa2+NEDBHATPNENECOMTαRβRα2RNE(-)SignalRegulation of Norepinephrine Synthesis and Metabolism:Uptake-1Normetanephrine (NMN)7Degradation of Catecholamines:HOHOCH2NHCH3OHCHEpinephrineHOHOCH2NH2OHCHNorepinephrineHOHOCH2NH2CH2DopamineHOHOCOOHOHCHDihydroxymandelic acid(DOMA)HOCH3OCOOHOHCH3-Methoxy-4-hydroxy-mandelic acid(VMA)*CH3OHOCH2NHCH3OHCHMetanephrineHOCH2NH2OHCHNormetanephrine(NMN)CH3OHOHOCOOHCH2Dihydroxyphenylacetic acid(DOPAC)CH3OHOCH2NH2CH23-MethoxytyramineCH3OHOCOOHCH2Homovanillic acid(HVA)COMTCOMTCOMTCOMTCOMTMAOMAOMAOMAOMAOMAODBHPNMTAdrenalmedullaCOMT = catechol-O-methyltransferaseMAO = monoamine oxidase*Diagnosis of pheochromocytoma( - )Pargyline, NialamidePre-synapticPost-synapticCa2+Na+TyrosineCellular messengersand effectsDiffusion, metabolismTyrosineDopaTHDDDopamine(DA)NEDBHATPCa2+NEDBHATPNENECOMTNormetanephrine (NMN)αRβRα2RNE(-)SignalMAO: associated with outer surface of mitochondia, includingthose within the terminals of adrenergic fibers.COMT: located mostly in cytoplasm. Rich in liver, kidney; notfound in adrenergic neurons. VMA: vanillylmandelic acid (3-Methoxy-4-hydroxymandelic acid)8Drug intervention -- Cholinergic transmissionPrecursor transportSynthesisHemicholiniumsStorageVesamicolReleaseBotulinum toxinDegradationby AchEReceptor+ actionAchCholinergic agonists(direct acting)CarbacholOxotremorine(Rate-limiting)AntiChEReversible (neostigmine)Irreversible (organo-phosphate)↓ : Stimulatory⊥ : InhibitorySolid: AgonisticDotted: AntagonisticCholinergic antagonistsAtropine