Canadian Association of Neurosciences Review: The Role of Dopamine Receptor Function in Neurodegenerative Diseases

Abstract

18 Dopamine (DA) is the predominant catecholamine neurotransmitter in the mammalian brain, where it controls various functions: endocrine regulation, food intake, cognition, emotion, addiction and locomotion.1 This catecholamine also plays multiple roles in the periphery as a modulator of the cardiovascular system, catecholamine release, hormone secretion, vascular tone, renal function, and gastrointestinal motility. These physiological effects are all mediated through DA receptors (D1-D5) which are members of the large family of G protein-coupled receptors.1,2 DA receptors can be subdivided into D1 and D2 classes: the D1-like receptor subfamily which includes D1 and D5 receptors, and the D2-like subfamily, which includes D2, D3 and D4 receptors. D1 and D2 receptors constitute major DA receptor subtypes that are expressed differentially in various regions of the human brain. The intensity and duration of these effects are primarily regulated by the rapid reuptake of DA by the plasma membrane DA transporter (DAT) back into presynaptic DA neurons.3-8 DAT is a member of the NaCl 2 -coupled neurotransmitter transporter family, which constitutes plasma membrane transporters for serotonin and ABSTRACT: Dopamine (DA) receptors, which are heavily expressed in the caudate/putamen of the brain, represent the molecular target of several drugs used in the treatment of various neurological disorders, such as Parkinson's disease. Although most of the drugs are very effective in alleviating the symptoms associated with these conditions, their long-term utilization could lead to the development of severe side-effects. In addition to uncovering novel mediators of physiological DA receptor functions, recent research advances are suggesting a role of these receptors in toxic effects on neurons. For instance, accumulating evidence indicates that DA receptors, particularly D1 receptors, are central in the neuronal toxicity induced by elevated synaptic levels of DA. In this review, we will discuss recent findings on DA receptors as regulators of long term neuronal dysfunction and neurodegenerative processes. RÉSUMÉ:Les récepteurs dopaminergiques, exprimés notamment dans les noyaux caudé et putamen du cerveau, sont la cible pharmacologique de plusieurs médicaments employés dans le traitement de maladies neurologiques telle que la maladie de Parkinson. Bien que ces médicaments soient efficaces pour renverser les symptômes cliniques de la maladie, ils sont associés au développement d'effets secondaires incommodants majeurs lorsque utilisés à long terme. L'avancement de la recherche sur la fonction des récepteurs dopaminergiques a mis en lumière plusieurs nouvelles voies de signalisation, dont certaines sont reconnues pour initier la neurodégénérescence. Ainsi, des études récentes ont démontré l'implication des récepteurs dopaminergiques D1 dans la toxicité induite par des niveaux synaptiques élevés de dopamine. Cet article a pour but d'exposer le rôle potentiel d'un dérèglement de la signalisation des récepteurs dopaminergiques dans l'a...

Reduced cortical neurotransmitter receptor complex levels in fetal Down syndrome brain

“…b Western blot from the SDS-PAGE using an antibody against the D1 receptor. The D1 receptor has been implicated as a crucial factor in neurodegenerative diseases (Lebel et al 2007) [e.g., Parkinson's disease, (Rinne et al 1985;Hisahara and Shimohama 2011) Huntington's disease, (Tang et al 2007) schizophrenia (Seeman et al 1989;Goldman-Rakic et al 2004) and Alzheimer's disease] in which D1 presents with abnormal striatal D1 but not D2 receptors and with a decreased density of D1 receptors in the hippocampus (Cortes et al 1988). In the flow (unbound material eluting from IP) no signal for the D1 receptor was observed or psychomotor effects (Seeman et al 1989).…”

The Time Course of D1 Agonist Induced Striatonigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

“…6, 4, 4, 4, 4 for control, 15, 30, 60, 120 The normal functioning of basal ganglia is dependent on the activity of the "direct" (striatonigral) and "indirect" (striatopallidal) output pathways subserved predominantly by the D1 and D2 receptor subtypes [10,11]. Degeneration of the nigrostriatal DA pathway results in an imbalance of the activity of the direct and indirect projecttion pathways and is thought to be responsible for the movement disorders associated with Parkinson's disease [3,7,11]. There are approximately an equal number of direct and indirect striatal projection neurons, which together constitute >90% of the neuron populations in the striatum [45].…”

“…Dopamine (DA) is involved in many physiological functions including motor control, mood and reward pathways [1][2][3][4][5][6][7]. DA receptors constitute a subfamily of G-protein coupled receptors (GPCRs) and are classified into two main subtypes D1 and D2 [8,9].…”

Molecular and cellular events of dopamine D1 receptor‐mediated tau phosphorylation in SK‐N‐MC cells

“…In fact, whether the hyperphosphorylation of tau subsequent to receptor activation results in a gain of toxicity is unknown in these conditions. Interestingly, selective D1 receptor activation has been associated with neurodegenerative processes in neuronal culture models (Chen et al, 2003; Lebel et al, 2007; Moussa et al, 2006). Dopamine mediated‐NMDA receptors phosphorylation, activation of the ERK signaling pathway, and increased levels of cdk5 are some of the mechanisms propose to be involved in D1 receptor mediated cellular dysfunction and neurodegeneration (Lebel et al, 2007).…”

“…Interestingly, selective D1 receptor activation has been associated with neurodegenerative processes in neuronal culture models (Chen et al, 2003; Lebel et al, 2007; Moussa et al, 2006). Dopamine mediated‐NMDA receptors phosphorylation, activation of the ERK signaling pathway, and increased levels of cdk5 are some of the mechanisms propose to be involved in D1 receptor mediated cellular dysfunction and neurodegeneration (Lebel et al, 2007). Our hypothesis is that alterations in the phosphorylation levels of tau might underlie the neuronal damage induced by D1 receptor activation reported in cell culture models.…”