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UIC PCOL 425 - Autonomic Nervous System - Introduction to neurotransmitter and receptor specificity

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Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 40Slide 41Slide 42Slide 43Slide 44Slide 45Slide 46Slide 47Slide 48Slide 49Slide 50Slide 51Slide 52Slide 53Slide 54Slide 55Slide 56Slide 57Slide 58Autonomic Nervous System:Introduction to neurotransmitter and receptor specificityThomas GuenthnerProfessor of PharmacologyCollege of MedicineTel. 996-7635Room E418, CMWE-mail: [email protected] to Dr. Richard Ye for Powerpoint concepts and slidesIdentify the key conceptual similarities and differences between autonomic cholinergic and adrenergic pathways including receptor subtypes, neurotransmitters, transmitter synthesis, storage, and release, and relative specificities of drugs that stimulate or inhibit each branch or activity. Knowledge objectives introduced by these two lectures:List the major systems or organs innervated by the autonomic cholinergic and adrenergic systems. Describe the organ system effects of cholinergic and adrenergic stimulation or antagonism. Relate the tissue expression profiles of cholinergic and adrenergic receptors to their specific functions.• 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 use Ach (nicotinic or muscarinic). Dopaminergic innervation in sympathetic system – renal blood vessels.Pre-synapticnerve cellPost-synapticnerve cellSynapticcleftCa2+Na+Precursors(choline/tyrosine)Synapse – site most amenable to pharmacologic manipulation:PrecursorNeurotransmitterStorageReleaseRecognitionby receptorsMetabolicdispositionManipulation possible at pre-synaptic neuron, where neurotransmitter is synthesized, stored and released upon cell activation, or at post-synaptic neuron or effector cell, where neurotransmitter is detected and its action is translated into cellular activities.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 effectiveBlock reuptake increases synaptic neurotransmitter concentrations Can be selective or non-selectiveInterfere with metabolism: Can be reversible or irreversible; blocking metabolism increases effective neurotransmitter concentrationsInterfere with recognition: Receptor antagonists & agonists; high specificityReleaseReuptakeAgonist: (1) A natural ligand that activates a receptor. (2) A drug that has properties similar to a natural ligand in activating the same receptor.Antagonist: (1) A receptor-specific blocker. (2) A molecule, such as a drug (e.g., enzyme inhibitor) or a physiologic agent (e.g., hormone), that diminishes or prevents the action of another molecule.Direct-acting: Molecule that physically binds to the target for its effect.Example: carbachol activates cholinergic receptors.Indirect-acting: Molecule that exerts effect on the target by interacting withanother non-target site.Example:neostigmine blocks AchE, causing Ach accumulation.Definition of Agonist and Antagonist:Mode of Action:Mode of action and agonism are different concepts. For example, a direct- acting molecule can be either agonistic or antagonistic.•Discovered that stimulation of the vagus of a frog heart causes release of a substance that, when applied to a second heart, could slow heart rate. He called this “Vagusstoff”, demonstrating the chemical basis of neurotransmission.Otto Loewi (Nobel Laureate, 1936)• Also found that atropine can prevent the inhibitory action, but not the release, of “Vagusstoff”.• Exposure of “Vagusstoff” to frog heart homogenate inactivates it.• Physostigmine enhances the effect of vagus stimulation on the heart, and prevents the destruction of “Vagusstoff”.Synthesis 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 M)CholineRecognitionby receptorsCa2+AchAchAchNerveimpulseNNNMAchAc-CoAChATAchAchEAchE choline+ acetic acidCAT = choline acetyltransferaseAchE = acetylcholinesteraseSynapticcleftAntiporterCH3COOH+AchE(CH3)3 N+–CH2–CH2–OH(CH3)3 N+–CH2–CH2–O–C–CH3OH2OOH(-)AchEGlu202Tyr337Ser203Glu334His447Degradation 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 acidDrug intervention -- Cholinergic transmissionPrecursor transportSynthesisHemicholiniumStorageVesamicolReleaseBotulinum toxinDegradationby AchEReceptor+ actionAchCholinergic agonists(direct acting)CarbacholPilocarpine(Rate-limiting)AntiChEReversible (neostigmine)Irreversible (organo- phosphate) : Stimulatory : InhibitorySolid: AgonisticDotted: AntagonisticCholinergic antagonistsAtropine (anti-M)Succinylcholine (anti-NM)Trimethaphan (anti-NN)Physostigmine’s effect on acetylcholine receptor is indirect. This effect is mediated through the inhibition of cholinesterase, which causes an increase in the local concentration of acetylcholine. The net effect is agonistic on acetylcholine receptor. An example of indirect-acting pharmacological agents:HOHOCH2NHCH3OHCHEpinephrineHOHOCH2NH2OHCHNorepinephrineHOHOCH2NH2CH2DopamineHOHOHCNH2CH2DOPACOOHHOHCNH2CH2TyrosineCOOHTHDD (L-AAD)DBHPNMTAdrenal medullaSynthesis of CatecholaminesTyrosine hydroxylaseDopa decarboxylase (L-amino acid


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UIC PCOL 425 - Autonomic Nervous System - Introduction to neurotransmitter and receptor specificity

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