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© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD

Advanced Neurotransmitters & Neuroglia

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

February 2017 MRC2.CORP.D.00209

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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

© PsychU. All rights reserved.


• Neurotransmitter Receptor Subtypes

• Neurotransmitter Circuitry and Biosynthesis

• Functional Connectivity of Monoaminergic Neurotransmitters

• Morphology and Function of Neuroglia

• Neuroglia Cell Types

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Table of Contents



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Neurotransmitter receptor subtypes

Neurotransmitter Receptor subtypes

Acetylcholine1 Cholinergic receptors: muscarinic receptors (M1-5 subtypes), nicotinic receptors

Histamine1 Histaminic receptors (H1-3 subtypes)

Dopamine1 Dopaminergic receptors (D1-5 subtypes)

Noradrenaline1,2 α-adrenergic receptors (α1A, B, D, α2A-C subtypes)β-adrenergic receptors (β1-3 subtypes)

Serotonin3 5-HT receptors (5-HT1A-B, 5-HT1D-F, 5-HT2A-C, 5-HT3-7 subtypes)

Glutamate1,4 Ionotropic receptors: non-NMDA (AMPA, kainate), NMDA receptorsMetabotropic receptors (mGluRs)

GABA1 GABAA, GABAB, and GABAC receptors

Neurotransmitters and Receptors*

*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. 3rd edition. Sinauer Associates; 2004.

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.



Neurotransmitter: Acetylcholine

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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. 3rd edition. Sinauer Associates; 2004.

Muscarinic receptors:(G protein-coupled)M1-Type: 1, 3, 5M2-Type: 2, 4

Neuronal nicotinic receptors:(Ligand-gated ion channels)

Group II: α7Group III-1: α2, α3, α4, α6Group III-2: β2, β4Group III-3: β3, α5

Circuitry1 Synthesis2

S

Glucose

PyruvateOAcetyl CoAC CH3CoA +HO CH2 CH2 N (CH3)3

Choline acetyltransferaseAcetylcholine

+

C O CH2CH3 CH2 N+

O

(CH3)3

Choline

Media septal nucleusin basal forebrain

Receptors1

Image based on: Brichta L, et al; 20131



Neurotransmitter: Histamine1

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H1, histamine receptor H1; H2, histamine receptor H2; H3, histamine receptor H3. 1. Purves D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.

Circuitry Synthesis

Histaminic receptors:(G protein-coupled) H1, H2, H3

Tuberomammillary nucleus of hypothalamus

CH2

COO

NH3

+

_

Histidine

CO2

Histidinedecarboxylase

CH2 NH3

+Histamine

Receptors

Image based on: Purves D, et al; 20041

HN N

HN N

CH

CH2



Neurotransmitter: Dopamine

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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. 3rd edition. Sinauer Associates; 2004; Brichta L, et al. Trends Neurosci. 2013;36(9):543-554.

Circuitry1

Dopamine receptors:(G protein-coupled)

D1-like: D1, D5D2-like: D2, D3, D4

Synthesis1

NH3

TyrosinehydroxylaseHO

CH2 CH NH3

COO_

O2

HO

CH2 CH

COO_

NH3

OH

CO2

+

+

HO

CH2 CH2

OH

+

Tyrosine

Dihydroxyphenylalanine(DOPA)

Dopamine

DOPAdecarboxylase

Substantia nigra and ventral tegmental area

Receptors2




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Neurotransmitter: NorepinephrineCircuitry1 Synthesis1

Adrenergic receptors:(G protein-coupled)

α1A, α1B, α1Dα2A, α2B, α2Cβ1, β2, β3

CH2HO

HO

CH

OH

NH2

HO

CH2 CH2 NH2HO

Dopamine

Norepinephrine

Dopamine β-hydroxylase

Locus coeruleus

Receptors2


α1A, alpha-1A adrenergic receptor; α1B, alpha-1B adrenergic receptor; α1D, alpha-1D adrenergic receptor; α2A, alpha-2A adrenergic receptor; α2B, alpha-2B adrenergic receptor; α2C, alpha-2C adrenergic receptor; β1, beta-1 adrenergic receptor β2, beta-2 adrenergic receptor; β3, beta-3 adrenergic receptor.

1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004; 2. Brichta L, et al. Trends Neurosci. 2013;36(9):543-554.



Neurotransmitter: Serotonin

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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. 3rd 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, 1F5-HT2A, 2C 5-HT4, 5-HT5, 5-HT6, 5-HT7Ligand-gated ion channel:5-HT3

N

N

O2

CH2 CH NH3

COO_

Tryptophan

Tryptophan-5-hydroxylase

CH2 CH

COO_

HO

CO2

5-Hydroxy-tryptophan

Aromatic L-amino aciddecarboxylase

+

NH3

+

CH2 CH2

N

HO NH3+

Serotonin

Raphe nuclei

Receptors2




Neurotransmitter: Glutamate

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1. Brichta L, et al. Trends Neurosci. 2013;36(9):543-554; 2. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.

AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; mGLuR, metabotropic glutamate receptors; NMDA, N-methyl-D-aspartate.


H3N CH NH2

GlutamineCOO

CH2 CH2

_

C+

GlutamateCH2

COO

CH CH2

_

COO_+

H3N

O

Glutaminase

Metabotropic (mGluR):(G protein-coupled)Group I: 1,5Group II: 2,3Group III: 4,6,7,8

Ionotropic:NMDAAMPAKainate

Receptors1,2

Image based on: Brichta L, et al: 20132



Neurotransmitter: GABA

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1. Carlsson A. Int Clin Psychopharmacol. 1995;10(Suppl 3):21-28; 2. Purves D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.


CH2

Glucose

Glutamate COO

CH CH2 CH2

_

COO_

H3N+

Glutamic acid decarboxylase+ pyridoxal phosphate

GABACH2 CH2 COO

_+H3N

GABA receptors:

Ionotropic:GABAA, GABAC

Metabotropic:GABAB

Receptors2

Image based on: Carlsson A, et al; 19951

GABAA , gamma-aminobutyric acid type A receptor; GABAB, gamma-aminobutyric acid type B receptor; GABAC , gamma-aminobutyric acid type C receptor.



Functional Connectivity Across Monoamine Systems1

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5-HT, serotonin; 5-HT1A, serotonin 1A receptor; 5-HT1B, 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.

DA

5-HT

NE

Postsynapticneuron

D2 receptorα1 receptor

α2 receptor5-HT1A receptor5-HT1B receptor

GABAergic interneuron

Reuptake transporter

Image based on: Blier P; 20141



1. Purves D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.

• 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

Neuroglia1

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Types of Neuroglia1,2

1. Designua. Digital image 34221006. 123RF website. Accessed 09 December 2016. Available at: http://www.123rf.com/photo_34221006_stock-vector-neurons-and-neuroglial-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.

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Image from Designua 20161, with contextual support provided by Purves 20042



• Although there are similarities among neurotransmitter subtypes (eg monoamines, amino acids), substantial differences exist in each neurotransmitter’s neuroanatomical expression and synthesis1–4

• Due to the functional connectivity of neurotransmitter systems, alterations in one system can impact the others5

• Neuroglia perform several key functions relating to the metabolic and physical support of neurons6

Summary

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1. Purves D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.2. Brichta L, et al. Trends Neurosci. 2013;36(9):543-5543. 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.


© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD

Advanced Neurotransmitters & Neuroglia

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

February 2017 MRC2.CORP.D.00209

16

advanced neurotransmitters & neuroglia - psychu.org · • neuroglia perform several key...

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