Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A1-A2A Receptor Heteromers
The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By mean...
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| Veröffentlicht in: | The Journal of neuroscience 2006-02, Vol.26 (7), p.2080-2087 |
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| creator | Ciruela, Francisco Casado, Vicent Rodrigues, Ricardo J Lujan, Rafael Burgueno, Javier Canals, Meritxell Borycz, Janusz Rebola, Nelson Goldberg, Steven R Mallol, Josefa Cortes, Antonio Canela, Enric I Lopez-Gimenez, Juan F Milligan, Graeme Lluis, Carme Cunha, Rodrigo A Ferre, Sergi Franco, Rafael |
| description | The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine. |
| doi_str_mv | 10.1523/JNEUROSCI.3574-05.2006 |
| format | Article |
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In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.3574-05.2006</identifier><identifier>PMID: 16481441</identifier><language>eng</language><publisher>United States: Soc Neuroscience</publisher><subject>Adenosina ; Adenosine ; Animals ; Caffeine - pharmacology ; Cell Line ; Corpus Striatum - physiology ; Dimerization ; Humans ; Male ; Neurotransmissors ; Neurotransmitters ; Presynaptic Terminals - drug effects ; Presynaptic Terminals - physiology ; Rats ; Rats, Sprague-Dawley ; Receptor, Adenosine A1 - genetics ; Receptor, Adenosine A1 - metabolism ; Receptor, Adenosine A1 - physiology ; Receptors, Adenosine A2 - genetics ; Receptors, Adenosine A2 - metabolism ; Receptors, Adenosine A2 - physiology ; Recombinant Proteins - metabolism ; Synaptic Transmission - drug effects ; Synaptic Transmission - physiology ; Transfection</subject><ispartof>The Journal of neuroscience, 2006-02, Vol.26 (7), p.2080-2087</ispartof><rights>cc-by-nc-sa (c) Ciruela Alférez, Francisco et al., 2006 info:eu-repo/semantics/openAccess <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/es">http://creativecommons.org/licenses/by-nc-sa/3.0/es</a></rights><rights>Copyright © 2006 Society for Neuroscience 0270-6474/06/262080-08$15.00/0 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c305t-bf59373bfc8caed76448fdb81375f06e61ab704ce75a9190238f8d4126bbfdb53</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6674939/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6674939/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,26951,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16481441$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ciruela, Francisco</creatorcontrib><creatorcontrib>Casado, Vicent</creatorcontrib><creatorcontrib>Rodrigues, Ricardo J</creatorcontrib><creatorcontrib>Lujan, Rafael</creatorcontrib><creatorcontrib>Burgueno, Javier</creatorcontrib><creatorcontrib>Canals, Meritxell</creatorcontrib><creatorcontrib>Borycz, Janusz</creatorcontrib><creatorcontrib>Rebola, Nelson</creatorcontrib><creatorcontrib>Goldberg, Steven R</creatorcontrib><creatorcontrib>Mallol, Josefa</creatorcontrib><creatorcontrib>Cortes, Antonio</creatorcontrib><creatorcontrib>Canela, Enric I</creatorcontrib><creatorcontrib>Lopez-Gimenez, Juan F</creatorcontrib><creatorcontrib>Milligan, Graeme</creatorcontrib><creatorcontrib>Lluis, Carme</creatorcontrib><creatorcontrib>Cunha, Rodrigo A</creatorcontrib><creatorcontrib>Ferre, Sergi</creatorcontrib><creatorcontrib>Franco, Rafael</creatorcontrib><title>Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A1-A2A Receptor Heteromers</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. 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Casado, Vicent ; Rodrigues, Ricardo J ; Lujan, Rafael ; Burgueno, Javier ; Canals, Meritxell ; Borycz, Janusz ; Rebola, Nelson ; Goldberg, Steven R ; Mallol, Josefa ; Cortes, Antonio ; Canela, Enric I ; Lopez-Gimenez, Juan F ; Milligan, Graeme ; Lluis, Carme ; Cunha, Rodrigo A ; Ferre, Sergi ; Franco, Rafael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c305t-bf59373bfc8caed76448fdb81375f06e61ab704ce75a9190238f8d4126bbfdb53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adenosina</topic><topic>Adenosine</topic><topic>Animals</topic><topic>Caffeine - pharmacology</topic><topic>Cell Line</topic><topic>Corpus Striatum - physiology</topic><topic>Dimerization</topic><topic>Humans</topic><topic>Male</topic><topic>Neurotransmissors</topic><topic>Neurotransmitters</topic><topic>Presynaptic Terminals - drug effects</topic><topic>Presynaptic Terminals - physiology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor, Adenosine A1 - genetics</topic><topic>Receptor, Adenosine A1 - metabolism</topic><topic>Receptor, Adenosine A1 - physiology</topic><topic>Receptors, Adenosine A2 - genetics</topic><topic>Receptors, Adenosine A2 - metabolism</topic><topic>Receptors, Adenosine A2 - physiology</topic><topic>Recombinant Proteins - metabolism</topic><topic>Synaptic Transmission - drug effects</topic><topic>Synaptic Transmission - physiology</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ciruela, Francisco</creatorcontrib><creatorcontrib>Casado, Vicent</creatorcontrib><creatorcontrib>Rodrigues, Ricardo J</creatorcontrib><creatorcontrib>Lujan, Rafael</creatorcontrib><creatorcontrib>Burgueno, Javier</creatorcontrib><creatorcontrib>Canals, Meritxell</creatorcontrib><creatorcontrib>Borycz, Janusz</creatorcontrib><creatorcontrib>Rebola, Nelson</creatorcontrib><creatorcontrib>Goldberg, Steven R</creatorcontrib><creatorcontrib>Mallol, Josefa</creatorcontrib><creatorcontrib>Cortes, Antonio</creatorcontrib><creatorcontrib>Canela, Enric I</creatorcontrib><creatorcontrib>Lopez-Gimenez, Juan F</creatorcontrib><creatorcontrib>Milligan, Graeme</creatorcontrib><creatorcontrib>Lluis, Carme</creatorcontrib><creatorcontrib>Cunha, Rodrigo A</creatorcontrib><creatorcontrib>Ferre, Sergi</creatorcontrib><creatorcontrib>Franco, Rafael</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>Recercat</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ciruela, Francisco</au><au>Casado, Vicent</au><au>Rodrigues, Ricardo J</au><au>Lujan, Rafael</au><au>Burgueno, Javier</au><au>Canals, Meritxell</au><au>Borycz, Janusz</au><au>Rebola, Nelson</au><au>Goldberg, Steven R</au><au>Mallol, Josefa</au><au>Cortes, Antonio</au><au>Canela, Enric I</au><au>Lopez-Gimenez, Juan F</au><au>Milligan, Graeme</au><au>Lluis, Carme</au><au>Cunha, Rodrigo A</au><au>Ferre, Sergi</au><au>Franco, Rafael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A1-A2A Receptor Heteromers</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2006-02-15</date><risdate>2006</risdate><volume>26</volume><issue>7</issue><spage>2080</spage><epage>2087</epage><pages>2080-2087</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><abstract>The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.</abstract><cop>United States</cop><pub>Soc Neuroscience</pub><pmid>16481441</pmid><doi>10.1523/JNEUROSCI.3574-05.2006</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosina Adenosine Animals Caffeine - pharmacology Cell Line Corpus Striatum - physiology Dimerization Humans Male Neurotransmissors Neurotransmitters Presynaptic Terminals - drug effects Presynaptic Terminals - physiology Rats Rats, Sprague-Dawley Receptor, Adenosine A1 - genetics Receptor, Adenosine A1 - metabolism Receptor, Adenosine A1 - physiology Receptors, Adenosine A2 - genetics Receptors, Adenosine A2 - metabolism Receptors, Adenosine A2 - physiology Recombinant Proteins - metabolism Synaptic Transmission - drug effects Synaptic Transmission - physiology Transfection |
| title | Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A1-A2A Receptor Heteromers |
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