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Autonomic Nervous System: Introduction to neurotransmitter and receptor specificity Thomas Guenthner Professor of Pharmacology College of Medicine Tel.

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Presentation on theme: "Autonomic Nervous System: Introduction to neurotransmitter and receptor specificity Thomas Guenthner Professor of Pharmacology College of Medicine Tel."— Presentation transcript:

1 Autonomic Nervous System: Introduction to neurotransmitter and receptor specificity Thomas Guenthner Professor of Pharmacology College of Medicine Tel Room E418, CMW Thanks to Dr. Richard Ye for Powerpoint concepts and slides

2 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.

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6 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.

7 Pre-synaptic nerve cell Post-synaptic nerve cell Synaptic cleft Ca 2+ 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.

8 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 Reuptake

9 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.

10 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”.

11 Synthesis of acetylcholine: CH 3 N+N+ –CH 2 –CH 2 –OH CoA–S–C–CH 3 O Choline Acetyl-CoA + Choline acetyltransferase CH 3 N+N+ –CH 2 –CH 2 –O –C–CH 3 O CoA-SH + CoA Acetylcholine

12 Synthesis, storage and release of acetylcholine: Pre-synaptic cell Post-synaptic cell Ach Ca 2+ Na + Choline (10  M) Choline Recognition by receptors Ca 2+ Ach Nerve impulse N NMNM Ach Ac-CoA ChAT Ach AchE choline + acetic acid CAT = choline acetyltransferase AchE = acetylcholinesterase Synaptic cleft Antiporter

13 CH 3 COOH + AchE (CH 3 ) 3 N + –CH 2 –CH 2 –OH (CH 3 ) 3 N + –CH 2 –CH 2 –O –C–CH 3 O H2OH2O 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 CholineAcetic acid

14 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-N M ) Trimethaphan (anti-N N )

15 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 agonism:

16 HO CH 2 NHCH 3 OH CH Epinephrine HO CH 2 NH 2 OH CH Norepinephrine HO CH 2 NH 2 CH 2 Dopamine HO HC NH 2 CH 2 DOPA COOH HO HC NH 2 CH 2 Tyrosine COOH TH DD(L-AAD) DBHPNMT Adrenal medulla Synthesis of Catecholamines Tyrosine hydroxylase Dopa decarboxylase (L-amino acid decarboxylase) Dopamine  -hydroxylase Phenylethanolamine- N-methyl transferase 1 3 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.

17 Pre-synaptic Post-synaptic Ca 2+ Na + Tyrosine Cellular messengers and effects Diffusion, metabolism Tyrosine Dopa TH DD Dopamine (DA) NE DBH ATP Ca 2+ NE DBH ATP NE COMT RR RR RR NE (-) Signal Regulation of Norepinephrine Synthesis and Metabolism: Uptake-1 Normetanephrine (NMN)

18 Drug intervention -- Adrenergic transmission Tyrosine Dopa  DA Metyrosine Vesicle (DA  NE) Reserpine Release Bretylium, guanethidine Recapture by Uptake-1 Receptor + action NE Adrenergic agonists (direct acting) Isoproterenol Albuterol (Rate-limiting) Cocaine Tricyclic antidepressants (e.g. imipramine) Adrenergic antagonists Phentolamine (  -blocker) Propranolol (  -blocker) TH Amphetamine, tyramine, ephedrine  : Stimulatory  : Inhibitory Solid: Agonistic Dotted: Antagonistic

19 PNS Receptor Functions

20 PNS Receptors - Pharmacological Classification: Cholinergic R Adrenergic R Dopamine R Muscarinic R Nicotinic R M 1, M 3, M 5 (Gq coupled) M 2, M 4 (Gi coupled) N M (neuromuscular, or muscle type) N N (neuronal, or ganglion type)  1, 22  1,  2,  D 1, D 2, D 3, D 4, D 5 Other receptors (receptors for NANC transmitters, e.g. nitric oxide, vasoactive intestinal peptide, neuropeptide Y) (mAChR) (nAChR)

21 Thoracolumbar Cranial Sacral CNSPre-ganglionicGanglionPost-ganglionic Parasympathetic Ach Nicotinic Ach Nicotinic Ach Nicotinic Ach Nicotinic Ach Nicotinic Epi Sympathetic Sympathetic (adrenal medulla) Motor (somatic) Ach Muscarinic NE Adrenergic (  ) D Dopaminergic (D 1 ) Ach Nicotinic Cardiac & smooth muscles, gland cells, nerve terminals Cardiac & smooth muscles, gland cells, nerve terminals Sweat glands Renal vascular smooth muscle Released into blood Skeletal muscle Ach = acetylcholineNE = norepinephrineEpi = epinephrineD = dopamine Effectors

22 Adrenergic receptors

23 Classification of adrenergic receptors by agonist potency  -- NE  Epi > Iso  -- Iso > Epi > NE NE = norepinephrine Epi = epinephrine Iso = isoproterenol HO CH 2 NHCH 3 OH CH Epi HO CH 2 NH 2 OH CH NE HO CH 2 NH OH CH Iso CH(CH 3 ) 2

24 Agonist Signaling properties of adrenergic receptors Agonist 11 22  1,2,3 GqGiGs  Inositol phosphates (IP3)  Diacyl glycerol (DAG)  cAMP  cAMP  Calcium channels  K+ conductance Mostly excitatory Mostly inhibitory Mostly excitatory Norepinephrine Epinephrine Phenylephrine Norepinephrine Methyl NE Clonidine Isoproterenol Albuterol (  2) Dobutamine (  1)

25 Gs and Gi proteins have different functions Agonist  ss Agonist  iiAC ss ii Gs = stimulatory G protein Gi = inhibitory G protein AC = adenylyl cyclase (convert ATP to cAMP) Beta1 receptor Alpha2 receptor

26  1 : postsynaptic effector cells, especially smooth muscle Vasoconstriction, hepatic glycogenolysis  2 presynaptic adrenergic nerve terminals (autoreceptor), platelets, lipocytes, 0 smooth muscle Inhibition of transmitter release, platelet aggregation, relaxation of gi smooth muscle  1 postsynaptic effector cells: heart, lipocytes, brain, presynaptic adrenergic / cholinergic terminals Increased cardiac rate & force, relaxation of gastrointestinal smooth muscle  2 postsynaptic effector cells: smooth muscle, cardiac muscle Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis  postsynaptic effector cells: lipocytes Lipolysis Distribution and functions of adrenergic receptors:

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29 Propranolol Pindolol Acebutolol Nadolol Metoprolol Atenolol  1 antagonistic  half-life  1 and  2 antagonistic  half-life   2 antagonistic effect  1 antagonistic Partial  2 agonistic  1 antagonistic Partial  2 agonistic

30 Dopaminergic receptors

31 HO CH 2 NHCH 3 OH CH Epinephrine HO CH 2 NH 2 OH CH Norepinephrine HO CH 2 NH 2 CH 2 Dopamine HO HC NH 2 CH 2 DOPA COOH HO HC NH 2 CH 2 Tyrosine COOH TH DD(L-AAD) DBHPNMT Tyrosine hydroxylase Dopa decarboxylase (L-amino acid decarboxylase) Dopamine  -hydroxylase Phenylethanolamine- N-methyl transferase 1 3

32 Dopaminergic receptors in the periphery Dopamine receptors play important roles in CNS. Notably, dopamine neurotransmission is involved in several diseases including Parkinson’s disease, schizophenia, and attention deficiency disorder. There are 5 types of dopamine receptors (D1 – D5). In periphery, D1 dopamine receptor mediates renal vasodilation, and increased myocardial contractility. Agonist D2,3,4 D1,5 GiGs  cAMP  cAMP

33 Cholinergic receptors

34 “Nicotinic actions” -- similar to those induced by nicotine; action mediated by nicotinic cholinergic receptors: stimulation of all autonomic ganglia (N N ) stimulation of voluntary muscle (N M ) secretion of epinephrine from the adrenal medulla (N N ) Cholinergic receptors: Nicotinic Nicotiana tabacum (cultivated tobacco)

35 Nicotinic acetylcholine receptor: Function Ligand-gated ion (Na + ) channel - an “Ionotropic Receptor” Acetylcholine binds to the  -subunits of the receptor making the membrane more permeable to cations (sodium) and causing a local depolarization. The local depolarization spreads to an action potential, or leads to muscle contraction when summed with the action of other receptors. The ion channel is open during the active state. Nicotine in small doses stimulates autonomic ganglia and adrenal medulla. When large doses are applied, the stimulatory effect is quickly followed by a blockade of transmission.

36 Nicotinic receptor antagonists Competitive vs. depolarizing Competitive Physically blocks Ach binding INHIBITOR Depolarizing Binds and locks the receptor open

37 “Muscarinic actions” -- reproduced by injection of muscarine, from Amanita muscaria (fly agaric). Similar to those of parasympathetic stimulation Neural/enteric (M 1 ): CNS, ENS, gastric parietal cells (excitatory; Gq) Cardiac (M 2 ): atria & conducting tissue; presynaptic (inhibitory; Gi) Glandular/endothelial (M 3 ): exocrine glands, vessels (excitatory; Gq) Neural (M 4 ): CNS (inhibitory; Gi) Neural (M 5 ): CNS (excitatory; Gq) (Sites of primary expression are listed; all are found in CNS) Cholinergic receptors: Muscarinic Multiple muscarinic cholinergic receptors distributed in different tissues. Therefore, the “muscarinic actions” are dependent on the receptors in different tissues and cells.

38 Agonist Muscarinic acetylcholine receptors – G Protein-Coupled Receptors (“Metabotropic” Receptors) Agonist M1 (enteric, neuronal) M2 (cardiac) M3 (glandular, vascular ) GqGi  IP3, DAG (Depolarization) (Stimulation)  Intracellular Ca2+  cAMP  Ca2+ channel  K + conductance  K + conductance Mostly excitatory CNS excitation Gastric acid secretion Gastrointestinal motility Mostly inhibitory Cardiac inhibition Presynaptic inhibition Neuronal inhibition Glandular secretion Contraction of visceral smooth muscle Vasodilation (via NO) (Slow IPSP) (Inhibition) M5 (CNS) M4 (CNS)

39 Intracellular signaling triggered by acetylcholine in the Heart Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase

40 Clinical manifestation of excessive cholinergic effects D – Defecation U – Urination M – Miosis B – Bradycardia E – Emesis L – Lacrimation S – Salivation (DUMBELS)

41 Effects of muscarinic antagonists “DRY AS A BONE, RED AS A BEET, MAD AS A HATTER.” Decreased sweating, salivation and lacrimation Reflex peripheral (cutaneous) vasodilation to dissipate heat (hyperthermia) CNS effects of muscarinic inhibition -- restlessness, delerium, hallucination ALSO: Bronchodilation Tachycardia Mydriasis (pupil dilation) and Cycloplegia (loss of focus) GI and Bladder atony

42 Physiological Effects of ANS Stimulation and Inhibition

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44 Receptor distribution and effects in the autonomic nervous system: OrganReceptorParasympatheticReceptor Heart Rate  Force  Automaticity  Force   Rate  Force  Conduction velocity  AV block M2M2M2M2M2M2 Arterioles SA node Atrial muscle AV node Ventricular muscle Blood vessels Coronary Skeletal muscle Viscera Skin Brain Erectile tissue Salivary gland Contraction Relaxation Contraction Relaxation  Vein M3M3M3M3 Sympathetic (Continued, next page) M3M3

45 OrganSympatheticReceptorParasympatheticReceptor Relaxation Motility  Contraction Relaxation Viscera Bronchiolar SMC Glands GI track Smooth muscle Sphincters Glands Uterus         Secretion Motility  Relaxation Secretion Gastric acid secretion Variable M3M3M3M3M1M3M3M3M3M1 Skin Pilomotor SMC Contraction (piloerection)  Salivary glandsSecretion     SecretionM3M3 Lacrimal glandsSecretionM3M3 KidneyRenin release  Liver Glycogenolysis Gluconeogenesis   Fat Lipolysis  M3M3 Contraction From: Rang et al. Pharmacology, 6 th Ed. p Also, see Katzung, Basic & Clinical Pharmacology, 10 th Ed. p.86.

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47 Cardiovascular Pharmacology (Blood Pressure)

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49 Cardiovascular effects of intravenous infusion of epinephrine, norepinephrine, and isoproterenol in man. Norepinephrine (predominantly  -agonist) causes vasoconstriction and increased systolic and diastolic BP, with a reflex bradycardia. Isoproterenol (  -agonist) is a vasodilator, but strongly increases cardiac force and rate. Mean arterial pressure falls. Epinephrine combines both actions.

50 Two kinds of effects produced by Ach. A. Ach causes a fall in BP due to vasodilation. B. A larger dose of Ach also produces bradycardia, further reducing BP. C. Atropine blocks the effect of Ach in lowering BP. D. Still under the influence of atropine, a much larger dose of Ach causes a rise in BP and tachycardia. Sir Henry Hallett Dale (Nobel laureate, 1936) A, B: Muscarinic effects of Ach (M 3, M 2 ) C: Muscarinic antagonistic effect (M) D. Stimulation of sympathetic ganglia (N N ) (Arterial pressure of an anesthetized cat was measured)

51 Receptor distribution and effects in the autonomic nervous system: OrganReceptorParasympatheticReceptor Heart Rate  Force  Automaticity  Force   Rate  Force  Conduction velocity  AV block M2M2M2M2M2M2 Arterioles SA node Atrial muscle AV node Ventricular muscle Blood vessels Coronary Skeletal muscle Viscera Skin Brain Erectile tissue Salivary gland Contraction Relaxation Contraction Relaxation  Vein M3M3M3M3 Sympathetic (Continued, next page) M3M3

52 Intracellular signaling triggered by acetylcholine in the endothelium eNOS ● NO L-Arg L-Citruline Major molecular players: M3, heterotrimeric G Protein Gq, Ca(2+)-CaM, eNOS, NO eNOS Nitric oxide synthase

53 Nitric oxide (NO) signaling pathway for SMC relaxation Second messenger Inhibition of PDE causes sustained level of cGMP that maintains SMC relaxation. Sildenafil (Viagra) is an inhibitor for PDE 5.

54 Pulmonary Pharmacology (Asthma and COPD)

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57 Ocular Pharmacology (Glaucoma)

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59 Lens Pupillary dilator muscle (   ) Pupillary constrictor muscle (M 3 ) Secretion of aqueous humor (  ) (M 3 ) Cholinergic effects:Adrenergic effects: Contraction of pupillary constrictor muscle -- miosis Contraction of ciliary muscle - bulge of lens -- near vision,  outflow of aqueous humor Contraction of pupillary dilator muscle -- mydriasis Stimulation of ciliary epithelium --  production of aqueous humor Trabecular meshwork (opened by pilocarpine)


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