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The Human D2 Dopamine Receptor Synergizes with the A2A Adenosine Receptor to Stimulate Adenylyl Cyclase in PC12 Cells

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The Human D2 Dopamine Receptor Synergizes with the A2A Adenosine Receptor to Stimulate Adenylyl Cyclase in PC12 Cells Neuropsychopharmacology (2003) 28, 1317–1327 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org The Human D2 Dopamine Receptor Synergizes with the A2A Adenosine Receptor to Stimulate Adenylyl Cyclase in PC12 Cells Oliver Kudlacek1, Herwig Just1, Vladimir M Korkhov1, Nina Vartian1, Markus Klinger1, Halyna 1 1 1 ,1 1 Pankevych , Qiong Yang , Christian Nanoff , Michael Freissmuth* and Stefan Boehm 1Institute of Pharmacology, University of Vienna, A-1090 Wien, Austria The adenosine A receptor and the dopamine D receptor are prototypically coupled to G and G /G , respectively. In striatal 2A 2 s i o intermediate spiny neurons, these receptors are colocalized in dendritic spines and act as mutual antagonists. This antagonism has been proposed to occur at the level of the receptors or of receptor–G protein coupling. We tested this model in PC12 cells which endogenously express A2A receptors. The human D2 receptor was introduced into PC12 cells by stable transfection. A2A-agonist- mediated inhibition of D2 agonist binding was absent in PC12 cell membranes but present in HEK293 cells transfected as a control. However, in the resulting PC12 cell lines, the action of the D agonist quinpirole depended on the expression level of the D receptor: at 2 2 low and high receptor levels, the A -agonist-induced elevation of cAMP was enhanced and inhibited, respectively. Forskolin-stimulated 2A cAMP formation was invariably inhibited by quinpirole. The effects of quinpirole were abolished by pretreatment with pertussis toxin. A2A-receptor-mediated cAMP formation was inhibited by other Gi/Go-coupled receptors that were either endogenously present (P2y12- like receptor for ADP) or stably expressed after transfection (A1 adenosine, metabotropic glutamate receptor-7A). Similarly, voltage 2+ activated Ca channels were inhibited by the endogenous P2Y receptor and by the heterologously expressed A1 receptor but not by the D receptor. These data indicate functional segregation of signaling components. Our observations are thus compatible with the 2 proposed model that D and A receptors are closely associated, but they highlight the fact that this interaction can also support 2 2A synergism. Neuropsychopharmacology (2003) 28, 1317–1327, advance online publication, 30 April 2003; doi:10.1038/sj.npp.1300181 2+ Keywords: A2A adenosine receptor; D2 dopamine receptor; adenylyl cyclase isoforms; voltage-activated Ca channel; rap1 INTRODUCTION targeted knockout of the gene) or depletion of dopamine impairs locomotion, and this dysfunction can be amelio- In the central nervous system, adenosine and dopamine act rated by the administration of A antagonists (see Aoyama as neuromodulators that bind to G-protein-coupled recep- 2A et al, 2000; Grondin et al, 1999; earlier references in tors and impinge on fast synaptic transmission by Richardson et al, 1997). (ii) Activation of A receptors inhibitory and excitatory amino acids. Both the G /G - 2A s olf induces catalepsy (Ferre´ et al, 1991a) as do D antagonists. coupled A adenosine receptor and the G /G -coupled D 2 2A i o 2 Conversely, catalepsy induced by blockage of D receptors dopamine receptor are enriched in the corpus striatum and 2 is reversed by A antagonists (Hauber et al, 2001). (iii) The in mesolimbic areas, such as the nucleus accumbens and the 2A induction of the immediate-early gene c-fos by D2 lateral septum (Svenningsson et al, 1999). In these brain antagonists is attenuated by blockage of A receptors; this regions, the two receptors are mostly colocalized, and 2A effect is confined to neurons where the receptors are various types of interactions between A and D receptor 2A 2 coexpressed (Pinna et al, 1999). Taken together, these ligands reveal a functional link between these two proteins: results indicate that there is a functional antagonism (i) Blockage of D2 receptors (eg by neuroleptic drugs or by between A2A and D2 receptors (Ferre´ et al, 1997). In line with these experimental data, both retrospective epidemio- *Correspondence: Dr M Freissmuth, Institute of Pharmacology, logical evidence (Fredholm et al, 1999; Benedetti et al, 2000 University of Vienna, Waehringer Str.13A, A-1090 Wien, Austria, and references therein) as well as prospective cohort studies Tel: +43 1 4277 64171, Fax: +43 1 4277 9641, E-mail: [email protected] (Ross et al, 2000; Ascherio et al, 2001) indicate that Received 22 May 2002; revised 10 February 2003; accepted 20 blockage of A2A receptors by caffeine intake reduces the risk February 2003 of people to develop Parkinson’s disease. Similarly, the Online publication: 27 February 2003 at http://www.acnp.org/citations/ adenosine uptake inhibitor dipyridamol enhances the Npp022702197/default.pdf antipsychotic activity of the D2 antagonist haloperidol Synergistic interaction of A2A- and D2-receptor O Kudlacek et al 1318 (Akhondzadeh et al, 2000). Thus, A2A receptor ligands have (XAC), haloperidol, and pertussis toxin were purchased been recognized as novel therapeutic agents for illnesses from Sigma Chemical Co. (St Louis, MO), and CGS21680 (2- 0 typically treated with D2 receptor ligands. [p-(2-carboxyethyl)phenethylamino]-5 -N-ethylcarboxami- The functional antagonism between D2 and A2A receptors doadenosine) from Tocris (Bristol, UK). Affinity-purified has been proposed to reflect the ability of the A2A receptor rabbit antiserum against rap1/Krev-1 was from Santa Cruz to impair high-affinity agonist binding to the D2 receptor by Biotechnology (Santa Cruz, CA). Immunofluorescence was a membrane-delimited process. This effect was originally performed with anti-c-myc antibody (Santa Cruz Biotech- observed in rat striatal membranes (Ferre´ et al, 1991b), and nology), anti-FLAG antibody M2 (Stratagene, La Jolla, CA), subsequently also documented upon heterologous expres- anti-HA antibody 16B12 (kind gift of E Ogris, Vienna sion of the receptors in fibroblast cell lines (Ltk-murine Biocenter), Cy3-coupled goat anti-rabbit (Amersham, Buck- fibroblasts in Dasgupta et al, 1996; Chinese hamster ovary inghamshire, UK), and FITC-coupled goat anti-mouse cells in Kull et al, 1999). Agonist occupancy of the A2A (Jackson, West Grove, PA). receptor blunted high-affinity agonist binding to the D2 receptor in the absence of GTP; hence, the effect was Cell Culture and Transfection proposed to be accounted for by an interaction at the level of the receptors or of receptor–G protein complexes. While PC12 cells were plated onto collagen-coated culture dishes this model explains the antagonistic action of the A2A (Biomedical Technologies Inc., Stoughton, MA, USA), adenosine receptor, several observations, however, cannot propagated in Opti-Mem medium containing 10% (vol/ be accounted for by simple reciprocal antagonism at the vol) horse serum, 5% (vol/vol) FCS, 0.2 mM L-glutamine, level of these two receptors. Most importantly, mice lacking 25 000 U/l penicillin G, and 25 mg/l streptomycin. Media for A2A receptors display a hypodopaminergic phenotype culture of stably transfected cells were supplemented with (Dassesse et al, 2001); similarly, stimulation of the striatal 0.2 mg/ml geneticin (G418) in order to maintain the A2A receptor fails to elevate cAMP in mice that are deficient selection pressure. Transfection of PC12 cells and of s in D2 receptors (Zahniser et al, 2000). These findings may HEK293 was performed using lipofection (TransFast , reflect adaptive changes that occur during development to Promega, Madison, WI) and CaPO4-precipitation, respec- cope with the targeted deletion of the respective genes. tively. The plasmids employed encoded the wild type and Alternatively, they may indicate that the interaction epitope-tagged versions of the human D2 dopamine (Bofill- between the A2A receptor and the D2 receptor is not solely Cardona et al, 2000), the FLAG-tagged metabotropic mutually antagonistic. In the present work, we employed glutamate receptor-7A (mGluR7A) (ElFar et al, 2001), the the neuroendocrine cell line PC12 to examine effector c-myc-tagged human A2A adenosine receptor (Klinger et al, regulation by the combined stimulation of the A2A 2002), and the HA-tagged A1 adenosine receptor; the latter adenosine and D2 dopamine receptor. PC12 cells can be was generated by PCR using a primer that extended the N- differentiated into a neuronal phenotype by nerve growth terminus by the nine amino acids (YPYDVPDYA) that factor. Our results demonstrate that D2 receptors can represent the major epitope of influenza hemaglutinin. The synergize with A2A receptors to stimulate cAMP accumula- integrity of the coding sequence was verified by fluorescent tion, a property that is not shared by other Gi/Go-coupled sequencing. After 48 h, geneticin (G418; 0.8 mg/ml) was receptors. added to the media to initiate selection for stably transfected cells. Receptor expression was checked by 3 125 binding ([ H]CCPA for the A1 receptor; [ I]epidepride MATERIAL AND METHODS for the D2 receptor) or by immunofluorescence (in Materials particular mGluR7A because a suitable radioligand is not available). Nontransfected PC12 cells did not contain PC12 cells were obtained from the European Collection of detectable amounts of A1 and D2 receptors (detection limit Cell Cultures (ECACC; Salisbury, UK). Collagen was from o10 fmol/mg) and did not respond to any of the receptor Biomedical Technologies Inc. (Stoughton, MA, USA). Hu- agonists (A1 ¼ CPA or R-PIA, D2 ¼ quinpirole, man b-nerve growth factor (NGF) was from R&D Systems mGluR7A ¼ L-AP4) employed. (CPA, N6-cyclopentyladeno- Inc. (Wiesbaden, Germany). Adenosine deaminase was sine;L-AP4 ¼ L-2-amino-4-phosphonobutanoic acid.) from Roche Molecular Biochemicals (Mannheim, Ger- Prior to the recording of ICa, PC12 cells were detached many). Optimem medium, L-glutamine, penicillin G, from culture dishes and replated at low density. In order streptomycin, horse serum, fetal calf serum (FCS), and to induce neuronal differentiation, PC12 cells were G418 (geneticin) were from Life Technologies (Grand exposed to recombinant human NGF (50 ng/ml) for 5–6 Island, NY). Centrifuge tubes and tissue culture plates were days.
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