Advanced Neurotransmitters & Neuroglia Otsuka Pharmaceutical Development & Commercialization, Inc. 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC. February 2017 MRC2.CORP.D.00209 1 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
This program was developed with the support of Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck, LLC. The speakers are either employees or paid contractors of Otsuka Pharmaceutical Development & Commercialization, Inc. 2 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
Table of Contents Neurotransmitter Receptor Subtypes Neurotransmitter Circuitry and Biosynthesis Functional Connectivity of Monoaminergic Neurotransmitters Morphology and Function of Neuroglia Neuroglia Cell Types 3
Neurotransmitters and Receptors* Neurotransmitter receptor subtypes Neurotransmitter Acetylcholine 1 Histamine 1 Dopamine 1 Noradrenaline 1,2 Serotonin 3 Glutamate 1,4 GABA 1 Receptor subtypes Cholinergic receptors: muscarinic receptors (M 1-5 subtypes), nicotinic receptors Histaminic receptors (H 1-3 subtypes) Dopaminergic receptors (D 1-5 subtypes) α-adrenergic receptors (α 1A, B, D, α 2A-C subtypes) β-adrenergic receptors (β 1-3 subtypes) 5-HT receptors (5-HT 1A-B, 5-HT 1D-F, 5-HT 2A-C, 5-HT 3-7 subtypes) Ionotropic receptors: non-nmda (AMPA, kainate), NMDA receptors Metabotropic receptors (mglurs) GABA A, GABA B, and GABA C receptors 5-HT, serotonin; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; D, dopamine; GABA, gamma-aminobutyric acid; H, histamine; M, muscarinic; mglurs, metabotropic glutamate receptors; NMDA, N-methyl-D-aspartate. *Common targets for drugs; will be discussed in further detail in disease-specific modules. 1. Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th edition. Cambridge University Press; 2013. 2. Quaglia W, et al. Expert Opin Ther Pat. 2011;21(4):455-81. 3. Polter AM, et al. Front Mol Neurosci. 2011;4:31. 4. Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004. 4
Neurotransmitter: Acetylcholine Circuitry 1 Synthesis 2 Glucose Pyruvate Acetyl CoA Choline O CoA S C CH 3 CH 2 CH 2 N (CH 3 ) 3 Choline acetyltransferase Acetylcholine O CH 3 C O CH 2 CH 2 N (CH 3 ) 3 Receptors 1 Muscarinic receptors: (G protein-coupled) M1-Type: 1, 3, 5 M2-Type: 2, 4 Media septal nucleus in basal forebrain Image based on: Brichta L, et al; 2013 1 Acetyl CoA, acetyl coenzyme A; M1, muscarinic acetylcholine receptor M1; M2, muscarinic acetylcholine receptor M2. 1. Brichta L, et al. Trends Neurosci. 2013;36(9):543-554. 2. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004. Neuronal nicotinic receptors: (Ligand-gated ion channels) Group II: α7 Group III-1: α2, α3, α4, α6 Group III-2: β2, β4 Group III-3: β3, α5 5
Neurotransmitter: Histamine 1 Circuitry Synthesis Histidine _ COO CH 2 CH NH 3 HN N Histidine decarboxylase Histamine CO 2 CH 2 CH 2 NH 3 HN N Receptors Histaminic receptors: (G protein-coupled) H1, H2, H3 Tuberomammillary nucleus of hypothalamus Image based on: Purves D, et al; 2004 1 H1, histamine receptor H1; H2, histamine receptor H2; H3, histamine receptor H3. 1. Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004. 6
Neurotransmitter: Dopamine Circuitry 1 Tyrosine Synthesis 1 Dihydroxyphenylalanine (DOPA) OH O 2 COO _ CH 2 CH NH 3 Tyrosine hydroxylase COO _ CH 2 CH NH3 DOPA decarboxylase Dopamine CO 2 CH 2 CH 2 NH 3 OH Receptors 2 Substantia nigra and ventral tegmental area Dopamine receptors: (G protein-coupled) Image based on: Purves D, et al; 2004 1 D1, dopamine receptor 1; D2, dopamine receptor 2; D3, dopamine receptor 3; D4, dopamine receptor 4, D5, dopamine receptor 5. 1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004; Brichta L, et al. Trends Neurosci. 2013;36(9):543-554. D1-like: D1, D5 D2-like: D2, D3, D4 7
Neurotransmitter: Norepinephrine Circuitry 1 Synthesis 1 CH 2 CH 2 NH 2 Dopamine Dopamine β-hydroxylase OH CH CH 2 NH 2 Norepinephrine Receptors 2 Locus coeruleus Adrenergic receptors: (G protein-coupled) α 1 A, α 1 B, α 1 D α 2 A, α 2 B, α 2 C β 1, β 2, β 3 Image based on: Purves D, et al; 2004 1 α 1 A, alpha-1a adrenergic receptor; α 1 B, alpha-1b adrenergic receptor; α 1 D, alpha-1d adrenergic receptor; α 2 A, alpha-2a adrenergic receptor; α 2 B, alpha-2b adrenergic receptor; α 2 C, alpha-2c adrenergic receptor; β 1, beta-1 adrenergic receptor β 2, beta-2 adrenergic receptor; β 3, beta-3 adrenergic receptor. 1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004; 2. Brichta L, et al. Trends Neurosci. 2013;36(9):543-554. 8
Neurotransmitter: Serotonin Circuitry 1 Synthesis 1 COO _ Tryptophan CH 2 CH NH 3 5-Hydroxytryptophan Tryptophan-5- hydroxylase O 2 Aromatic L-amino acid decarboxylase Serotonin N N N CO 2 Receptors 2 CH 2 COO _ CH CH 2 CH 2 NH 3 NH 3 Raphe nuclei Image based on: Purves D, et al; 2004 1 5-HT1A, serotonin 1A receptor; 1B, serotonin 1B receptor; 1D, serotonin 1D receptor; 1E, serotonin 1E receptor; 1F, serotonin 1F receptor; 5- HT2A, serotonin 2A receptor; 2C, serotonin 2C receptor; 5-HT3, serotonin 3 receptor; 5-HT4, serotonin 4 receptor; 5-HT5, serotonin 5 receptor; 5-HT6, serotonin 6 receptor; 5-HT7, serotonin 7 receptor. 1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004; 2. Brichta L, et al. Trends Neurosci. 2013;36(9):543-554. Serotonin receptors: G protein-coupled: 5-HT1A, 1B, 1D, 1E, 1F 5-HT2A, 2C 5-HT4, 5-HT5, 5-HT6, 5-HT7 Ligand-gated ion channel: 5-HT3 9
Neurotransmitter: Glutamate Circuitry 1 Synthesis 2 Glutamine _ COO O H 3 N CH CH 2 CH 2 C NH 2 Glutaminase Glutamate H 3 N _ COO CH CH 2 CH 2 COO _ Receptors 1,2 Metabotropic (mglur): (G protein-coupled) Group I: 1,5 Group II: 2,3 Group III: 4,6,7,8 Image based on: Brichta L, et al: 2013 2 Ionotropic: NMDA AMPA Kainate AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; mglur, metabotropic glutamate receptors; NMDA, N-methyl-D-aspartate. 1. Brichta L, et al. Trends Neurosci. 2013;36(9):543-554; 2. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004. 10
Neurotransmitter: GABA Circuitry 1 Synthesis 2 Glucose Glutamate H 3 N _ COO CH CH 2 CH 2 COO _ GABA H 3 N Glutamic acid decarboxylase pyridoxal phosphate CH 2 CH 2 CH 2 COO _ Receptors 2 GABA receptors: Ionotropic: GABA A, GABA C Metabotropic: GABA B Image based on: Carlsson A, et al; 1995 1 GABA A, gamma-aminobutyric acid type A receptor; GABA B, gamma-aminobutyric acid type B receptor; GABA C, gamma-aminobutyric acid type C receptor. 1. Carlsson A. Int Clin Psychopharmacol. 1995;10(Suppl 3):21-28; 2. Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004. 11
Functional Connectivity Across Monoamine Systems 1 5-HT NE Postsynaptic neuron DA D 2 receptor α1 receptor α2 receptor 5-HT 1A receptor 5-HT 1B receptor GABAergic interneuron Reuptake transporter 5-HT, serotonin; 5-HT 1A, serotonin 1A receptor; 5-HT 1B, serotonin 1B receptor; α1, alpha-1 adrenergic receptor; α2, alpha-2 adrenergic receptor; D2, dopamine receptor 2; DA, dopamine; GABA, gamma-aminobutyric acid; NE, norepinephrine. 1. Blier P. Int J Neuropsychopharmacol. 2014;17(7):997-1008. Image based on: Blier P; 2014 1 12
Neuroglia 1 Glia = glue in Greek Glia cells of the central nervous system (CNS) are called neuroglia Neuroglia are different than neurons: Smaller than neurons Do not have axons, dendrites or conduct nerve impulses Outnumber neurons in brain ~3:1 ratio Essential in maintaining homeostasis within CNS: Assist in nervous system repair and maintenance Assist in development of nervous system, insulating neurons, and providing metabolic functions for neurons characteristics 1. Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004. 13
Types of Neuroglia 1,2 Image from Designua 2016 1, with contextual support provided by Purves 2004 2 1. Designua. Digital image 34221006. 123RF website. Accessed 09 December 2016. Available at: http://www.123rf.com/photo_34221006_stock-vector-neurons-andneuroglial-cells-glial-cells-are-non-neuronal-cells-in-brain-there-are-different-types-o.html. 2. Purves D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004. 14
Summary Although there are similarities among neurotransmitter subtypes (eg monoamines, amino acids), substantial differences exist in each neurotransmitter s neuroanatomical expression and synthesis 1 4 Due to the functional connectivity of neurotransmitter systems, alterations in one system can impact the others 5 Neuroglia perform several key functions relating to the metabolic and physical support of neurons 6 1. Purves D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; 2004. 2. Brichta L, et al. Trends Neurosci. 2013;36(9):543-554 3. McCarthy MM, et al. Trends Neurosci. 2002;25(6):307-12. 4. Carlsson A. Int Clin Psychopharmacol. 1995;10 Suppl 3:21-8. 5. Blier P. Int J Neuropsychopharmacol. 2014;17(7):997-1008. 6. Linser PJ. J Neurosci. 1985;5(9):2388-96. 15
Advanced Neurotransmitters & Neuroglia Otsuka Pharmaceutical Development & Commercialization, Inc. 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC. February 2017 MRC2.CORP.D.00209 16 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.