11/10/16. Neurotransmitters and their Receptors. Professor Abercrombie, Chapter 6, Neuroscience, 4 th ed, D. Purves et el.

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Events from neurotransmitter release to postsynaptic excitation or

1 Chapter 6, Neuroscience, 4 th ed, D. Purves et el. Neurotransmitters and their Receptors Professor Abercrombie, 2016 Events from neurotransmitter release to postsynaptic excitation or inhibition Sequence of events involved in transmission at a typical chemical synapse 1

2 A neurotransmitter can affect the activity of a postsynaptic cell via ionotropic and metabotropic receptors Criteria That Define a Neurotransmitter 2

3 Examples of small-molecule and peptide neurotransmitters 3

4 Biogenic Amines Biogenic amines Acetylcholine Catecholamines Dopamine Norepinephrine Epinephrine Indolamines Serotonin (5HT) Histamine ACh is a Quaternary Amine Acetylcholine System 4

5 Cholinergic functions Two major nuclei pedunculopontine nucleus-projects to thalamus q involved in sleep and?dreaming nucleus basalis (substantia innominata or nucleus of meynert) q projects to cortex q involved in memory and learning q loss in Alzheimer s disease Acetylcholine metabolism in cholinergic nerve terminals Acetylcholine receptors Nicotinic Ligand gated Implicated in MG Muscarinic G-linked M 1 -M 5 Primary CNS Ach receptor 5

6 The general architecture of ligand-gated receptors The structure of the nach receptor/channel The structure of the nach receptor/channel (Part 1) 6

7 The structure of the nach receptor/channel (Part 2) Transmitter-Gated Channels All made of 5 subunits Example is the nicotinic acetylcholine receptor Myasthenia Gravis 7

8 Acetylcholine receptors Nicotinic Ligand gated Implicated in MG Muscarinic G-linked M 1 -M 5 Primary CNS Ach receptor Structure and function of metabotropic receptors Example of G-Protein Activation Of A Channel 8

9 Biogenic Amines Biogenic amines Acetylcholine Catecholamines Dopamine Norepinephrine Epinephrine Indolamines Serotonin (5HT) Histamine 9

Catecholamines only Norepinephrine and Dopamine are significant in CNS epinephrine is peripheral in the SNS Share a common synthesis to a point and metabolism Figure 6.

10 Catecholamines only Norepinephrine and Dopamine are significant in CNS epinephrine is peripheral in the SNS Share a common synthesis to a point and metabolism Figure 6.11 Neurons and their projections containing catecholamine neurotransmitters Catecholamines are synthesized in a multi-step pathway [tyrosine] ~ 50 um TH Km = ~ 20 um Rate-Limiting Step AADC Km = ~ 400 um DBH Km = ~ 5 mm 10

11 Dopamine Systems Dopamine functions extrapyramidal system initiation and maintenance of goal directed and reward mediated behaviors screen meaningful and nonmeaningful stimuli regulation of affect A Catecholamine Synapse 11

12 DA synaptic pharmacology Monoamine Oxidase (MAO) Monoamine metabolism MAO exist in 2 intracellular isoenzymes MAO A--- found throughout body q inactivates dietary tyramine in GI tract MAO B---found in CNS primarily COMT extracellular 12

13 Structure and function of metabotropic receptors 13

14 Biogenic Amines Biogenic amines Acetylcholine Catecholamines Dopamine Norepinephrine Epinephrine Indolamines Serotonin (5HT) Histamine Norepinephrine Systems Norepinephrine NE functions Dorsal Bundle and Median forebrain bundle orientation and arousal sleep-wake system autonomic function and anxiety reward and reinforcement affect Implicated in anxiety, mood, and drug addictions and withdrawal syndromes 14

15 A Catecholamine Synapse Structure and function of metabotropic receptors 15

16 Biogenic Amines Biogenic amines Acetylcholine Catecholamines Dopamine Norepinephrine Epinephrine Indolamines Serotonin (5HT) Histamine 16

17 Serotonergic Function Serotonergic System Aspects rate of serotonin limiting synthesis factor for serotonin synthesis is the availability of tryptophan to the neuron crosses the BBB via active transport 17

18 Serotonin metabolism O H N CH 2 H a. MAO b. Aldehyde dehygrogenase C CH 2 O H O H CH 2 a. b. O H N H 5 hydroxytryptamine (5HT) serotonin N H 5 hydroxyindole acetic acid (5HIAA) Structure and function of metabotropic receptors 18

19 Monoamine Hypothesis of Depression depression due to deficit of monoamines and mania due to excess 1. reserpine induced depression (prevents vesicular storage of monoamines). 2. amphetamine withdrawal 3. effect of antidepressants SSRIs Tricyclics (uptake inhibitors) MAOIs MAOIs irreversibly bind enzymes acute effect: increase levels of monoamines chronic effect? Structurallly similar to amphetamine have stimulant properties, followed by antidepressant Tricyclics inhibit reuptake of monoamines into terminal (not vesicles) Many have direct effects on receptors (mach, Histamine, NE) leading to toxic side effects Acute effects: block reuptake of NE and 5-HT reduce activity in Locus Coeruleus and Raphe Nuclei Chronic effects: down regulation of NE and 5-HT autoreceptors increased NE and 5-HT transmission 19

for 5-HT Other side effects: Serotonin Syndrome changes in mental status

20 Monoamine Uptake Inhibitors SSRIs No more efficacious than tricyclics (but much more well tolerated) Possibly less sedating, fewer anticholinergic effects Block reuptake of MA (slightly) more selective for 5-HT Other side effects: Serotonin Syndrome changes in mental status restlessness/jitteriness/anxiety tremor stuttering sexual dysfunction insomnia A Serotonin deficiency: If it were only so simple! 20

21 Pharmacotherapy of Depression Antidepressant agent classes Monoamine oxidase inhibitors (MAOIs) Tricyclic (TCAs) antidepressants - Norepinephrine/Serotonin reuptake inhibitors Selective norepinephrine reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs) The Lag Time Enigma and Antidepressant Action Not adequately explained by monoamine deficiency hypothesis of depression Hypothesis that pathogenesis and treatment of depression involves a plasticity/adaptation in relevant neuronal pathways 21

22 Neurotransmitters, Pt. 2 AMINO ACIDS GLUTAMATE GABA PEPTIDERGIC TRANSMISSION OPIOIDS AS AN EXAMPLE NOVEL TRANSMITTER MOLECULES NO ZINC Amino Acidergic System 22

23 Glutamate Fast excitatory synaptic transmission Epilepsy, Ischemic brain damage, Anxiety, Addiction GLU Metabolism Glutamate receptors Four basic types NMDA AMPA (Quisqualate) Kainate Metabotropic receptor Cooperativity Common feature is to depolarize RMP 23

is kicked out of the channel NMDA receptor is now in active state and calcium influx increases.

24 Ionotropic AMPA and NMDA Receptors & Fast Synaptic Excitation Glutamate receptor cooperativity NMDA receptor in inactive state has Mg++ ion blocking the calcium ion channel When RMP is depolarized by another receptor such as AMPA or Metabotropic receptor the Mg++ is kicked out of the channel NMDA receptor is now in active state and calcium influx increases. Excitotoxicity NMDA Channel And Magnesium NMDA channel will only open if the cell is depolarized. This depolarization often occurs by the activation of AMPA receptors 24

25 NMDA Receptor is Both Voltage- and Ligand-Gated GABA Major inhibitory neurotransmitter Epilepsy, Huntington s disease, Tardive dyskinesia, Alcoholism, Sleep disorders 25

26 Glutamate Synapse GABA Biochemistry GABA-A Receptor Complex 26

27 GABA-A Receptor Model mglur/gaba-b Receptor Topology Presynaptic GABA-B Actions 27

28 An Example, Endogenous Opiate Peptides - The Discovery Process Neuropeptides usually contain between 3 and 36 amino acids 28

29 Neuroactive Peptides Peptide Bond Endogenous Opioids A Discovery Process Endogenous Opiate Peptides 29

30 30

Prepropeptides - Signal Sequence Allows Translocation to ER

31 Synthesis of Peptide Transmitters Follows the Secretory Pathway - Precursors Made in ER and Processed in Golgi Complex Prepropeptides - Signal Sequence Allows Translocation to ER Propeptide - Sequence is Cleaved in ER. Further Enzymatic Modification in LDCV. 31

32 LDCV Assembled in Golgi Apparatus and Transported to the Synapse. 32

33 Opiate Receptors 33

34 Other Neurotransmitter Systems ATP Gases Nitric oxide (NO) Carbon monoxide (CO) Metals Copper Zinc Cannabinoid-like molecules 34

35 Nitric Acid A Diffusable Gas with Transmitter-Like Properties? Zinc in Brain 35

36 Zinc 36

37 Sedative-Hypnotics and Anxiolytics: GABA A agonists CNS Depressants Group of drugs that depress functioning of the CNS produce calming, drowsiness and sleep Alcohols Barbiturates Volatile General Anesthetics Antiepileptics Benzodiazepines General Concepts Most commonly abused drugs (excluding nicotine) sedative, tranquilizer, anxiolytic and hypnotic Potentiate the effects of each other Cross tolerant with each other Cross dependence Universally capable of causing dependence 37

38 GABA-A Receptor Model Heterogeneity of GABA A Receptors Underlie Diversity of Function 5 subunits, each of which have many subtypes: β: β 1 β 2 β 3 β 4a β 4b Determine GABA affinity α: α 1 α 2 α 3 α 4 α 5 α 6 Barbiturate binding γ: γ 1 γ 2S γ 2L γ 3 Enable BZ binding, 2L vs. 2S δ: δ Benzodiazepine insensitivity ρ: ρ 1 Highest in Retina Over 170,000 possible combinations GABA agonists Muscimol is a rigid GABA analog isolated from the hallucinogenic mushroom Amanita muscaria, it is one of the most selective and potent GABA agonists known. hyperthermia, pupil dilation, elevation of mood, difficulties in concentration, panilopia, anorexia, ataxia, catalepsy and hallucinations. Barbiturates (e.g., pentobarbital, phenobarbital) Benzodiazepines (e.g., diazepam, chlordiazepoxide) Ethanol Neuroactive steroids (e.g., allopregnanalone) 38

39 GABA antagonists Bicuculline is a competetive antagonist and a potent convulsive Picrotoxin non-competitive antagonist (blocks chloride channel) comes from E. Indian shrub Flumazenil is a benzodiazepine antagonist Inverse agonists: liquid anxiety Beta-Carbolines (e.g., DBI, DMCM) -Inverse agonists decrease the frequency of channel openings (anti-dui pill?) Are their endogenous inverse agonists (leading to anxiety disorders, for example)? Benzodiazepines produce anxiolytic, anticonvulsant, muscle-relaxant, and sedativeanesthetic properties. Although they have no direct effect on Cl- channel opeining, they increase the affinity of the receptor for GABA as well as the frequency of GABA-activated channel openings. 39

40 40

Neurotransmitter Systems III Neurochemistry. Reading: BCP Chapter 6

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