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Dopamine: Functions, Signaling, and Association with Neurological Diseases

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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Fig. 1

Modified from (Bilder et al. 2004)

Fig. 2
Fig. 3

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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Authors

Contributions

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.

Corresponding authors

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

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Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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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  • DOI: https://doi.org/10.1007/s10571-018-0632-3

Keywords

  • Dopamine pathway
  • Neurotransmitter
  • Central nervous system
  • Neurodegenerative diseases