Neurotransmitters acting on G-protein coupled receptors
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1 Neurotransmitters acting on G-protein coupled receptors Part 2: Serotonin and Histamine BIOGENIC AMINES Monoamines Diamine
2 Indolamines: Serotonin Basic Neurochemistry. FIGURE 15-1: Chemical structure of 5-hydroxytryptamine (5-HT; serotonin) and related indolealkylamines. The indole ring structure consists of the benzene ring and the attached five-member ring containing nitrogen. HO Besides being in the brain serotonin is also found in platelets. During platelet activation, serotonin is released into circulation and becomes a stimulus for platelet aggregation. Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
3 When you think of serotonin, what diseases and human emotions come to your mind? Ecstasy and Molly and LSD Substance Use Disorders Schizophrenia
4 Serotonin chemistry, localization and function Biosynthesis of Serotonin BH4 Please remember that AAAD is the same as DOPA decarboxylase
5 Metabolism of Serotonin (5HIAA) Please note that MAO (not COMT) is the only enzyme for inactivating serotonin. Also, There are two forms of MAO: MAO-A preferentially metabolizes NE and 5-HT while both MAOs (A and B) work for dopamine
6 Metabolism of Serotonin (5HIAA)
7 Localization of 5-HT neurons and their projections Localization of Serotonin Cell bodies of serotoninergic cells are localized in the midbrain raphe nuclei
8 Serotonin Neurotransmission: Physiology Phe, Tyr, Tryp, L-DOPA LNAAT
9 Properties of Serotonin transporters VMAT2 Proton antiporter Sodium symporter SERT is a presynaptic membrane transporter that is involved in reuptake of serotonin using the Na + gradient VMAT2 transports monoamines particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine from cellular cytosol into synaptic vesicles. VMAT2 preferentially transports dopamine so production of dopamine in 5-HT neurons could reduce the content of vesicular 5-HT.
10 Properties of Serotonin transporters VMAT2 VMAT1 MDMA MDMA: 3,4-Methylenedioxymethamphetamine (ecstasy) The substituted amphetamine fenfluramine acts on VMAT1 and is used as appetite suppressant Substituted amphetamines such as MDMA and fenfluramine stimulate the release of 5-HT from serotonergic terminals by blocking vesicular uptake and making SERT work on reverse
11 Actions of MDMA and Life-threatening Overdose People take the MDMA for the euphoric, intoxicating effects. Signs of ecstasy use include heightened sensory perception, and the tactile sense may be exaggerated. A person may want to be touched or want to touch things that feel good. A person going to clubs to dance will have their energy increased so they can dance all night. But the user may also experience nausea, chills or involuntary teeth clenching. Muscles may cramp and vision may blur or be otherwise disturbed. Overdose can result in serotonin syndrome: Symptoms include high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, and diarrhea. Body temperature can increase to greater than 41.1 C (106.0 F). Complications may include seizures, extensive muscle breakdown and even death
12 Serotonin Neurotransmission: Pharmacology Copyright 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
13 Serotonin Receptors Three main subtypes: 5-HT 1, 5-HT 2 and 5-HT 3
14 Serotonin 5-HT 1 Receptors 5-HT1 receptor family: Coupled to Gi 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F antimigraine e.g., buspirone
15 5-HT1 receptor autoradiography showing ligand binding sites 5-HT1B and 5HT1D 5-HT1F 5-HT1A
16
17 Serotonin 5-HT 2 Receptors 5-HT2 receptor family 5-HT2A, 5-HT2B, 5-HT2C, all coupled to Gp
18 Serotonin 5-HT 2 Receptors Clozapine, Olanzapine, Resperidone
19 5-HT2A receptor localization in the cortex and hippocampus Weber and Andrade, Frontiers in Neuroscience August 2010 Volume 4 Article 36
20 5-HT2A localization in the cortex and hippocampus Weber and Andrade, Frontiers in Neuroscience August 2010 Volume 4 Article 36
21 Serotonin 5-HT 3 Receptors 5-HT3 receptor family: ligand-gated ion channel 5-HT3A, 5-HT3B Antiemetic Ondansetron (Zofran) is extremely important to treat nausea caused by the use of chemotherapy and drugs used in general anesthesia.
22 Histamine is also a neurotransmitter in the brain i Histamine is also found and released from mast cells and gastric mucosa
23 Localization of histaminergic neurons in the brain Localization of histaminergic neurons in the tuberomammillary nucleus of the hypothalamus. These neurons project diffusely to the cortex and other CNS regions where they control state of arousal and other brain functions.
24 Biosynthesis and Metabolism of Histamine Histidine decarboxylase
25 Histamine receptors
26 Distribution of histamine receptors and their mrnas in the brain
27 Histamine receptor pharmacology Antagonist: Diphenhydramine (Benadryl) Antagonist: H2 blockers to reduce acid secretion Agonists for treating eating disorders and pain
28 Presynaptic H3 receptors inhibit synthesis and/or release of other neurotransmitters Guillermo Aquino-Miranda, Juan Escamilla-Sánchez, Raúl González-Pantoja, Antonio Bueno-Nava, José-Antonio Arias- Montaño Histamine H3 receptor activation inhibits dopamine synthesis but not release or uptake in rat nucleus accumbens Neuropharmacology, Volume 106, 2016,
29
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