Dopamine: Functions, Signaling, and Association with Neurological Diseases

Klein, Marianne O.; Battagello, Daniella S.; Cardoso, Ariel R.; Hauser, David N.; Bittencourt, Jackson C.; Correa, Ricardo G.

doi:10.1007/s10571-018-0632-3

Review Paper
Published: 16 November 2018

Dopamine: Functions, Signaling, and Association with Neurological Diseases

Cellular and Molecular Neurobiology volume 39, pages 31–59 (2019)Cite this article

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Abstract

The dopaminergic system plays important roles in neuromodulation, such as motor control, motivation, reward, cognitive function, maternal, and reproductive behaviors. Dopamine is a neurotransmitter, synthesized in both central nervous system and the periphery, that exerts its actions upon binding to G protein-coupled receptors. Dopamine receptors are widely expressed in the body and function in both the peripheral and the central nervous systems. Dopaminergic signaling pathways are crucial to the maintenance of physiological processes and an unbalanced activity may lead to dysfunctions that are related to neurodegenerative diseases. Unveiling the neurobiology and the molecular mechanisms that underlie these illnesses may contribute to the development of new therapies that could promote a better quality of life for patients worldwide. In this review, we summarize the aspects of dopamine as a catecholaminergic neurotransmitter and discuss dopamine signaling pathways elicited through dopamine receptor activation in normal brain function. Furthermore, we describe the potential involvement of these signaling pathways in evoking the onset and progression of some diseases in the nervous system, such as Parkinson’s, Schizophrenia, Huntington’s, Attention Deficit and Hyperactivity Disorder, and Addiction. A brief description of new dopaminergic drugs recently approved and under development treatments for these ailments is also provided.

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Abbreviations

AD:: Alzheimer’s disease
ADHD:: Attention deficit/hyperactivity disorder
ALDH:: Aldehyde dehydrogenase
BDNF:: Brain-derived neurotropic factor
CaMKII:: Calcium/calmodulin-dependent kinase II
cAMP:: Cyclic 3,5 adenine-monophosphate
CDK5:: Cyclin-dependent kinase 5
CK1:: Casein kinase 1
CK2:: Casein kinase 2
COMT:: Catechol-O-methyl transferase
CREB:: cAMP Response element-binding protein
CSF:: Cerebral spinal fluid
DAG:: Diacylglycerol
DARPP-32:: cAMP-Regulated phosphoprotein 32-kDa
DAT:: Dopamine transporter
DJ-1:: PARK7 (Parkinson disease protein 7)
DOPAC:: 3,4-Dihydroxyphenylacetic acid
DOPAL:: 3,4-Dihydroxyphenylaldehyde
ELKs:: Glutamine, leucine, lysine, and serine-rich protein
ERK:: Extracellular-signal regulated kinases
FDA:: US Food and Drug Administration
GABA:: γ-Amino butyric acid
GIRK:: G protein inwardly rectifying potassium channel
GPCR:: G protein-coupled receptor
GRK:: G protein-coupled receptor kinase
GSK3:: Glycogen synthase kinase 3
GSTM2:: Glutathione transferase
GTP:: Guanosine triphosphate
HVA:: Homovanillic acid
HD:: Huntington’s disease
HTT:: Huntingtin gene
IGF:: Insulin growth factor
IP3:: Inositol trisphosphate
JNK:: c-Jun kinase
L-DOPA:: Levodopa
LB:: Lewy bodies
LRRK2:: Leucine-rich repeat kinase 2
MAPK:: Mitogen-activated protein kinase
MAPT:: Microtubule-associated protein
MAT:: Monoamine transporter
MAO:: Monoamine oxidase
mTORC2:: mTOR complex 2
NAc:: Nucleus accumbens
NET:: Norepinephrine transporter
NMDA:: Glutamate N-methyl-d-aspartate
Parkin:: PRKN
PD:: Parkinson’s disease
PDPK1:: Phosphatidylinositol-dependent kinase 1
PIP2:: Phosphatidylinositol-2-phosphate
PIP3:: Phosphatidylinositol-3-phosphate
PKA:: Protein kinase A
PKC:: Protein kinase C
PLC:: Phospholipase C
PP1:: Protein phosphatase 1
PP2A:: Protein phosphatase 2A
PP2B:: Protein phosphatase 2B
RGS:: Regulators of G protein signaling
RIM:: Rab3a-interacting molecule
ROS:: Reactive oxygen species
RTK:: Receptor tyrosine kinase
SNCA:: α-Synuclein
STEP:: Striatal-enriched tyrosine phosphatase
SZ:: Schizophrenia
TAAR:: Trace amine-associated receptors
VMAT2:: Vesicular monoamine transporter
VTA:: Ventral tegmental area

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Acknowledgements

This review was supported by São Paulo State Foundation for the Support of Research (FAPESP, Brazil; Grant #2016/02224-1 to JCB, Grant #2017/17998-5 to MOK, and Grant #2017/18019-0 to ARC). DSB is a fellowship recipient of the Agency for the Advancement of Higher Education (CAPES, Brazil). JCB is a recipient of grants from the National Council for Scientific and Technological Development (CNPq, Brazil; Grant #426378/2016-4), CAPES, and the Comité Français d’Evaluation de la Coopération Universitaire avec le Brésil (French Committee for the Evaluation of Academic and Scientific Cooperation with Brazil; CAPES-COFECUB Grant #848/15). RGC was partially supported by a Special Visiting Researcher (PVE) grant from the “Science without Borders” Program (CAPES).

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Laboratory of Chemical Neuroanatomy, Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, 05508-000, Brazil
Marianne O. Klein, Daniella S. Battagello, Ariel R. Cardoso & Jackson C. Bittencourt
Center for Translational Neuroscience, Sanford Burnham Prebys (SBP) Medical Discovery Institute, 10901 North Torrey Pines Rd., La Jolla, CA, 92037, USA
David N. Hauser & Ricardo G. Correa
Center for Neuroscience and Behavior, Institute of Psychology, USP, São Paulo, Brazil
Jackson C. Bittencourt

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Marianne O. Klein
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Daniella S. Battagello
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Ariel R. Cardoso
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David N. Hauser
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Jackson C. Bittencourt
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Ricardo G. Correa
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In this review, all authors had full access to the data and take all responsibility for its integrity and accuracy. MOK, DSB, and ARC drafted the manuscript, under supervision of JCB and RGC. MOK and DSB conceptualized and designed the figures. DNH, JCB, and RGC made critical revisions of the manuscript for their relevant intellectual content. JCB and RGC obtained the funding. All authors read and approved the final manuscript.

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Correspondence to Jackson C. Bittencourt or Ricardo G. Correa.

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The authors declare that they have no conflict of interest.

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Marianne O. Klein and Daniella S. Battagello have contributed equally to the work.

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Klein, M.O., Battagello, D.S., Cardoso, A.R. et al. Dopamine: Functions, Signaling, and Association with Neurological Diseases. Cell Mol Neurobiol 39, 31–59 (2019). https://doi.org/10.1007/s10571-018-0632-3

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Received: 21 August 2018
Accepted: 02 November 2018
Published: 16 November 2018
Issue Date: 31 January 2019
DOI: https://doi.org/10.1007/s10571-018-0632-3

Keywords

Dopamine pathway
Neurotransmitter
Central nervous system
Neurodegenerative diseases