Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression
Sigma σ1 and σ2 receptors are targets of cocaine. Despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is unknown. Cocaine increases the level of dopamine, a key neurotransmitter in CNS motor control and reward areas. While the drug also affects d...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-02-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2018.00017/full |
| _version_ | 1818023503197110272 |
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| author | David Aguinaga David Aguinaga Mireia Medrano Mireia Medrano Ignacio Vega-Quiroga Katia Gysling Enric I. Canela Enric I. Canela Gemma Navarro Gemma Navarro Rafael Franco Rafael Franco |
| author_facet | David Aguinaga David Aguinaga Mireia Medrano Mireia Medrano Ignacio Vega-Quiroga Katia Gysling Enric I. Canela Enric I. Canela Gemma Navarro Gemma Navarro Rafael Franco Rafael Franco |
| author_sort | David Aguinaga |
| collection | DOAJ |
| description | Sigma σ1 and σ2 receptors are targets of cocaine. Despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is unknown. Cocaine increases the level of dopamine, a key neurotransmitter in CNS motor control and reward areas. While the drug also affects dopaminergic signaling by allosteric modulations exerted by σ1R interacting with dopamine D1 and D2 receptors, the potential regulation of dopaminergic transmission by σ2R is also unknown. We here demonstrate that σ2R may form heteroreceptor complexes with D1 but not with D2 receptors. Remarkably σ1, σ2, and D1 receptors may form heterotrimers with particular signaling properties. Determination of cAMP levels, MAP kinase activation and label-free assays demonstrate allosteric interactions within the trimer. Importantly, the presence of σ2R induces bias in signal transduction as σ2R ligands increase cAMP signaling whereas reduce MAP kinase activation. These effects, which are opposite to those exerted via σ1R, suggest that the D1 receptor-mediated signaling depends on the degree of trimer formation and the differential balance of sigma receptor and heteroreceptor expression in acute versus chronic cocaine consumption. Although the physiological role is unknown, the heteroreceptor complex formed by σ1, σ2, and D1 receptors arise as relevant to convey the cocaine actions on motor control and reward circuits and as a key factor in acquisition of the addictive habit. |
| first_indexed | 2024-12-10T03:45:21Z |
| format | Article |
| id | doaj.art-25499f4370fe4d03a1a8aa829777a829 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-10T03:45:21Z |
| publishDate | 2018-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-25499f4370fe4d03a1a8aa829777a8292022-12-22T02:03:27ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992018-02-011110.3389/fnmol.2018.00017325966Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor ExpressionDavid Aguinaga0David Aguinaga1Mireia Medrano2Mireia Medrano3Ignacio Vega-Quiroga4Katia Gysling5Enric I. Canela6Enric I. Canela7Gemma Navarro8Gemma Navarro9Rafael Franco10Rafael Franco11Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainDepartment of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, SpainCentro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainDepartment of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, SpainDepartment of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, ChileDepartment of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, ChileCentro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainDepartment of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, SpainCentro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainDepartment of Biochemistry and Physiology, Faculty of Pharmacy, Universitat de Barcelona, Barcelona, SpainCentro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainDepartment of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, SpainSigma σ1 and σ2 receptors are targets of cocaine. Despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is unknown. Cocaine increases the level of dopamine, a key neurotransmitter in CNS motor control and reward areas. While the drug also affects dopaminergic signaling by allosteric modulations exerted by σ1R interacting with dopamine D1 and D2 receptors, the potential regulation of dopaminergic transmission by σ2R is also unknown. We here demonstrate that σ2R may form heteroreceptor complexes with D1 but not with D2 receptors. Remarkably σ1, σ2, and D1 receptors may form heterotrimers with particular signaling properties. Determination of cAMP levels, MAP kinase activation and label-free assays demonstrate allosteric interactions within the trimer. Importantly, the presence of σ2R induces bias in signal transduction as σ2R ligands increase cAMP signaling whereas reduce MAP kinase activation. These effects, which are opposite to those exerted via σ1R, suggest that the D1 receptor-mediated signaling depends on the degree of trimer formation and the differential balance of sigma receptor and heteroreceptor expression in acute versus chronic cocaine consumption. Although the physiological role is unknown, the heteroreceptor complex formed by σ1, σ2, and D1 receptors arise as relevant to convey the cocaine actions on motor control and reward circuits and as a key factor in acquisition of the addictive habit.http://journal.frontiersin.org/article/10.3389/fnmol.2018.00017/fullacuteaddictioncAMPchronicdopamine D1 and D2 receptorsERK1/2 phosphorylation |
| spellingShingle | David Aguinaga David Aguinaga Mireia Medrano Mireia Medrano Ignacio Vega-Quiroga Katia Gysling Enric I. Canela Enric I. Canela Gemma Navarro Gemma Navarro Rafael Franco Rafael Franco Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression Frontiers in Molecular Neuroscience acute addiction cAMP chronic dopamine D1 and D2 receptors ERK1/2 phosphorylation |
| title | Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression |
| title_full | Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression |
| title_fullStr | Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression |
| title_full_unstemmed | Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression |
| title_short | Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression |
| title_sort | cocaine effects on dopaminergic transmission depend on a balance between sigma 1 and sigma 2 receptor expression |
| topic | acute addiction cAMP chronic dopamine D1 and D2 receptors ERK1/2 phosphorylation |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2018.00017/full |
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