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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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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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