Autocrine activation of adenosine A₁ receptors blocks D_1A but not D_1B dopamine receptor desensitization

Abstract

Adenosine is known to modulate dopamine responses in several brain areas. Here, we show that tonic activation of adenosine receptors is able to impede desensitization of D 1 dopamine receptors. As measured by cAMP accumulation in transfected COS-7 cells, long-term exposure to dopamine agonists promoted desensitization of D 1B receptor but not that of D 1A receptor. The inability of D 1A receptor to desensitize was a result of the adenosine present in culture medium acting through activation of adenosine A1 receptors. In the central nervous system, the purine nucleoside adenosine is a product of cell metabolism that is increased upon imbalance between energy supply and demand. Emphasis has been put on the beneficial role that adenosine plays to protect excitable tissues from the damage produced in pathological situations such as ischemia, inflammation or epilepsy (reviewed in Linden 2001). However, a general property of adenosine is to modulate neuronal responses and the efficiency of synaptic transmission in specific brain areas, in response to the metabolic status of the nervous system (Brundege and Dunwiddie 1997). In particular, adenosine has been reported to reinforce the action of GABA B receptors (Sodickson and Bean 1998) or to inhibit several effects of dopamine in the cortex and basal ganglia (reviewed in Ferré et al. 1997).The modulatory effects of adenosine on dopamine systems have been investigated for their relevance to human pathology such as schizophrenia and Parkinson's disease. These effects are caused by interactions between the adenosine and dopamine receptors. dopamine receptors are colocalized in medium-size neurones of the striatum belonging to direct striatonigral pathway (Ferré et al. 1996). Antagonistic interactions between A 1 receptors and D 1 receptors are illustrated by the inhibition promoted by A 1 receptor agonists on the motor activation induced by D 1 receptor agonists in the striatum (Ferré et al. 1994). Mechanisms of this inhibition may involve an A 1 receptorinduced decrease in binding affinity of agonists for D 1 dopamine receptor, as shown in membrane preparations of rat striatum, and in mouse fibroblast cells stably expressing A 1 and D 1 receptors (Ferré et al. 1997(Ferré et al. , 1998).An additional and novel mechanism of adenosine-mediated modulation of D 1 receptor activity is presented here. We show that upon tonic activation of adenosine A 1 receptors, the desensitization of D 1A dopamine receptor is strongly inhibited, an effect that does not occur for the D 1B dopamine receptor subtype. Materials and methodsCell culture and transfection COS-7 cells were grown in DMEM with 4.5 g/L glucose (Life Technologies) supplemented with 10% calf fetal serum (Dutscher) and

D5Dopamine Receptors are Required for Dopaminergic Activation of Phospholipase C

“…Within the striatum, the D 5 receptor is expressed predominantly in cholinergic interneurons, whereas D 1 receptors predominate in GABAergic neurons (Rivera et al, 2002;Centonze et al, 2003). Unlike the D 1 receptor, D 5 receptors do not form functional complexes with A 1 adenosine receptors (Le Crom et al, 2002), and plasma membrane localization of the D 5 (but not the D 1 ) receptor requires N-glycosylation (Karpa et al, 1999). These observations indicate significant structural differences between the receptor subtypes, and this is consistent with the recent observation of differential physicochemical susceptibility of G s -coupled versus G q -coupled D 1 -like sites to reducing agents or plasma membrane perturbations (Panchalingam and Undie, 2005).…”

Opposing effects of phorbol‐12‐myristate‐13‐acetate, an activator of protein kinase C, on the signaling of structurally related human dopamine D1 and D5 receptors

“…Studies have shown that D1R and D5R expressed in same heterologous expression systems can both undergo agonist‐induced desensitization (Jarvie et al . 1993; Le Crom et al . 2002).…”

Dopamine and Renal Function and Blood Pressure Regulation

“…Interestingly, A 1 R and D 1 R have been shown to physically interact in the central nervous system with the formation of a heteromeric complex that leads to the uncoupling of the D 1 R from its Gs-like protein complex (178,188). However, in COS-7 cells and fibroblasts heterologously expressing A 1 R, D 1 R, and D 5 R, activation of A 1 R blocks the desensitization of D 1 R but not D 5 R (348), another instance of cell specific effect or related to gene overexpression.…”