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Aging and disease    2015, Vol. 6 Issue (5) : 349-368     DOI: 10.14336/AD.2015.0330
Review Article |
Dopamine Receptors and Neurodegeneration
Claudia Rangel-Barajas1,2,*(), Israel Coronel3, Benjamín Florán4
1Department of Psychological and Brain Sciences Program in Neurosciences, Indiana University Bloomington, Bloomington, IN 47405, USA
2Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
3Health Sciences Faculty, Anahuac University, Mexico Norte, State of Mexico, Mexico.
4Department of Physiology, Biophysics and Neurosciences CINVESTAV-IPN, Mexico.
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Abstract  

Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson’s disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases.

Keywords Dopamine receptors      neurotoxicity      neurodegeneration      Parkinson’s disease     
Corresponding Authors: Claudia Rangel-Barajas     E-mail: crangelb@indiana.edu
About author:

present address: Kunming Biomed International, Kunming, Yunnan, 650500, China

Issue Date: 01 October 2015
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Claudia Rangel-Barajas
Israel Coronel
Benjamín Florán
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Claudia Rangel-Barajas,Israel Coronel,Benjamín Florán. Dopamine Receptors and Neurodegeneration[J]. Aging and disease, 2015, 6(5): 349-368.
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http://www.aginganddisease.org/EN/10.14336/AD.2015.0330     OR     http://www.aginganddisease.org/EN/Y2015/V6/I5/349
Figure 1.  The D1-like DA Receptors Intracellular Signal Pathways. Shows the DA mediated effects through D1-like DA receptors that by the activation of intracellular signals. Stimulatory effects are indicated with red arrows and inhibitory effects in blue line ended with a circle. cAMP, 3'-5'-cyclic adenosine monophosphate; αs/olf or αq ATP, active Gα protein; PKA, protein kinase A; DARPP-32, dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa; AC, adenylyl cyclase; PP1, PP2A or PP2B, protein-phosphatase 1, 2A or 2B; PKC, protein kinase C; PLC, phospholipase C; IP3, inositol triphosphate; mTOR, mammalian target of rapamycin; PIP2, phosphatidylinositol 2; Ca2+, calcium; MAPK, mitogen-activated protein kinase EPAC-GEF, guanine-nucleotide-exchange factor of Rap1; Rap1, Ras proximate 1. AMPA, α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA, N-methyl-D-aspartate; GABAA, γ-Aminobutyric acid A; CREB; cAMP response element-binding protein.
Figure 2.  The D2-like DA Receptors Intracellular Signal Pathways. Shows the DA mediated effects through D2-like DA receptors that occur by a complex activation of intracellular signals that are related with events such as neurodevelopment, proteasomal degradation, cell proliferation and cognitive process. Stimulatory effects are indicated with red arrows, dashed red arrow indicates plausible activation and inhibitory effects in blue line ended with a circle. cAMP, 3'-5'-cyclic adenosine monophosphate; αi/o ATP, active Gαi/o protein; PKA, protein kinase A; DARPP-32, dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa; AC, adenylyl cyclase; PP1, PP2A or PP2B, protein-phosphatase 1, 2A or 2B; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; Akt, thymoma viral proto-oncogene; GSK-3, Glycogen Synthase Kinase-3; PLCβ, phospholipase C isoform β; PI3K, phosphatidylinositol 3-kinase; PIP2, PIP3, phosphatidylinositol 2 and 3; IP3, inositol triphosphate; Ca2+, calcium ; GIRK, G protein coupled inward rectifier potassium; MEK; Raf,; ERK, extracellular signal-regulated kinase protein kinase; PDK, phosphoinositide-dependant kinase; mTOR, mammalian target of rapamycin; p70S6, p70S6 kinase; rpS6, ribosomal S6 protein; 4E-BP, eukaryotic initiation factor 4E-binding protein 1.
Figure 3.  Oxidative stress and Neurotoxicity. A. Shows the neurotoxic mechanisms of DA and neurotoxins used to mimic PD in the dopaminergic neuron. DA and the neurotoxins 6-hydroxydopmine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), cause reactive species of oxygen (ROS) affecting the mitochondrial function and lipoperoxidation and cytoskeletal disorganization, which leads energy crisis and neuronal death. MPTP is first incorporated into the glial cells and metabolized to MPP+, this metabolite can cross the membrane through the DA transporter (DAT) to reach intracellular compartments in DAergic neuron, while 6-OHDA can directly cross through DAT. B. Neurotoxicity by renin-angiotensin system (RAS) activation and DA receptors. In RAS, angiotensinogen is converted to Angiotensin I (AI) by renin, AI is converted into Angiotensin II (AII) thought angiotensin converting enzyme (ACE), AII mediate their actions by angiotensin receptors AT1 and AT2Rs. AT1Rs activate the nicotidamine adenine dinucleotide phosphate oxidase complex (NADPH), which is the major source of ROS causing mitochondrial dysfunction and inflammatory response. The interaction AT1Rs with of D1 and D3Rs increases the DA response while D5Rs can regulate the AT1Rs by proteasome mechanisms. DA receptors are also related with immune response in T cells.
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