Autonomic Nervous System Introduction to neurotransmitter and receptor specificity Thomas Guenthner Professor of Pharmacology College of Medicine Tel 996 7635 Room E418 CMW E mail tmg uic edu Thanks to Dr Richard Ye for Powerpoint concepts and slides Knowledge objectives introduced by these two lectures Identify 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 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 Pharmacological division of cholinergic vs adrenergic neurotransmission 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 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 Synapse site most amenable to pharmacologic manipulation Na Precursors choline tyrosine Synaptic cleft Precursor Neurotransmitter Pre synaptic nerve cell Storage Release Ca2 Recognition by receptors Metabolic disposition Post synaptic nerve cell Manipulation 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 Key Steps in Neurotransmission Synthesis Storage Action potential Metabolism Release Recognition action Reuptake Strategies for Pharmacological Intervention Block synthesis and storage Block release Block reuptake Interfere with metabolism Interfere with recognition Usually rate limiting steps produce long term effects Rapid action and effective increases synaptic neurotransmitter concentrations Can be selective or non selective Can be reversible or irreversible blocking metabolism increases effective neurotransmitter concentrations Receptor antagonists agonists high specificity Definition of Agonist and Antagonist Agonist 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 Mode of Action 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 with another non target site Example neostigmine blocks AchE causing Ach accumulation Mode of action and agonism are different concepts For example a directacting molecule can be either agonistic or antagonistic Otto Loewi Nobel Laureate 1936 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 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 Choline Acetylcholine CH3 CH3 CH3 CH3 N CH2 CH2 OH O CoA S C CH3 Acetyl CoA Choline acetyltransferase CH3 CH3 O N CH2 CH2 O C CH3 CoA SH CoA Synthesis storage and release of acetylcholine Na Choline 10 M Synaptic cleft Choline ChAT Ac CoA Ach Antiporter Ach Ach Nerve impulse Ach Ach Pre synaptic cell choline acetic acid NN Ca 2 AchE Ach Recognition by receptors Ca2 NM CAT choline acetyltransferase AchE acetylcholinesterase AchE Post synaptic cell Degradation of acetylcholine H2O O CH3 3 N CH2 CH2 O C CH3 Glu202 Tyr337 AchE AchE Choline Acetic acid CH3 3 N CH2 CH2 OH CH3COOH OH Ser203 Glu334 His447 600 000 Ach molecules AchE min turnover time of 150 microseconds 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 enzyme 4 Deacylation of AchE regeneration of enzyme Drug intervention Cholinergic transmission Rate limiting Precursor transport Hemicholinium Stimulatory Inhibitory Solid Agonistic Dotted Antagonistic Synthesis Cholinergic antagonists Atropine anti M Succinylcholine anti NM Trimethaphan anti NN Storage Vesamicol Release Botulinum toxin Cholinergic agonists direct acting AntiChE Carbachol Pilocarpine Ach Receptor action Degradation by AchE Reversible neostigmine Irreversible organophosphate An example of indirect acting pharmacological agents 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 Julius Axelrod Nobel Laureate 1970 His discoveries concern the mechanisms which regulate the formation of norepinephrine in the nerve cells and the mechanisms which are involved in the inactivation of this important neurotransmitter Synthesis of Catecholamines PhenylethanolamineN methyl transferase Tyrosine hydroxylase 3 1 CH2 HC COOH HO Tyrosine TH HO CH2 HC COOH HO NH2 DOPA NH2 DD L AAD OH HO CH HO CH2 Epinephrine OH PNMT HO CH HO CH2 NHCH3 NH2 Norepinephrine DBH HO CH2 HO CH2 Dopamine NH2 Adrenal medulla Dopamine hydroxylase Dopa decarboxylase L amino acid decarboxylase Regulation of Norepinephrine Synthesis and Metabolism Na Tyrosine Tyrosine TH Dopa DD R Dopamine DA Signal DBH ATP NE NE Uptake 1 R Ca 2 Pre synaptic DBH Post synaptic NE NE NE ATP Ca2 R Cellular messengers and effects CO MT Diffusion metabolism Normetanephrine NMN Drug intervention Adrenergic transmission Stimulatory Inhibitory Solid Agonistic Dotted Antagonistic Tyrosine Rate limiting
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