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

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1 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: [email protected] Thanks to Dr. Richard Ye for Powerpoint concepts and slides 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. 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.23 • 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. adrenergic neurotransmission • 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.4 Pre-synaptic nerve cell Post-synaptic nerve cell Synaptic cleft Ca2+ Na+ Precursors (choline/tyrosine) Synapse – site most amenable to pharmacologic manipulation: Precursor Neurotransmitter Storage Release Recognition by receptors Metabolic disposition 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. Synthesis & Storage Action potential Metabolism Recognition (action) Key Steps in Neurotransmission: Strategies for Pharmacological Intervention: Block synthesis and storage: Usually rate-limiting steps; produce long-term effects Block release: Rapid action and effective Block reuptake increases synaptic neurotransmitter concentrations Can be selective or non-selective Interfere with metabolism: Can be reversible or irreversible; blocking metabolism increases effective neurotransmitter concentrations Interfere with recognition: Receptor antagonists & agonists; high specificity Release Reuptake5 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. 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. 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”.6 Synthesis of acetylcholine: CH3 CH3 CH3 N+ –CH2–CH2–OH CoA–S–C–CH3 O Choline Acetyl-CoA + Choline acetyltransferase CH3 CH3 CH3 N+ –CH2–CH2–O –C–CH3 O CoA-SH + CoA Acetylcholine Synthesis, storage and release of acetylcholine: Pre-synaptic cell Post-synaptic cell Ach Ca2+ Na+ Choline (10 µM) Choline Recognition by receptors Ca2+ Ach Ach Ach Nerve impulse NN NM Ach Ac-CoA ChAT Ach AchE AchE choline + acetic acid CAT = choline acetyltransferase AchE = acetylcholinesterase Synaptic cleft Antiporter7 CH3COOH + AchE (CH3)3 N+–CH2–CH2–OH (CH3)3 N+–CH2–CH2–O –C–CH3 O H2O OH (-) AchE Glu202 Tyr337 Ser203 Glu334 His447 Degradation 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 enzyme 4. Deacylation of AchE (regeneration of enzyme) 600,000 Ach molecules / AchE / min = turnover time of 150 microseconds Choline Acetic acid Drug intervention -- Cholinergic transmission Precursor transport Synthesis Hemicholinium Storage Vesamicol Release Botulinum toxin Degradation by AchE Receptor + action Ach Cholinergic agonists (direct acting) Carbachol Pilocarpine (Rate-limiting) AntiChE Reversible (neostigmine) Irreversible (organo- phosphate) ↓ : Stimulatory ⊥ : Inhibitory Solid: Agonistic Dotted: Antagonistic Cholinergic antagonists Atropine (anti-M) Succinylcholine (anti-NM) Trimethaphan (anti-NN)8 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: HO HO CH2 NHCH3 OH CH Epinephrine HO HO CH2 NH2 OH CH Norepinephrine HO HO CH2 NH2 CH2 Dopamine HO HO HC NH2 CH2 DOPA COOH HO HC NH2 CH2 Tyrosine COOH TH DD (L-AAD) DBH PNMT Adrenal medulla Synthesis of Catecholamines Tyrosine hydroxylase Dopa decarboxylase (L-amino acid decarboxylase) Dopamine β-hydroxylase Phenylethanolamine- N-methyl transferase 1 3 Julius Axelrod (Nobel Laureate, 1970) His discoveries concern the


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