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Molecular integration takes place through allosteric receptor\u2013receptor interactions in heteroreceptor complexes of synaptic and extra-synaptic regions. It involves the modulation of receptor protomer recognition, signaling and trafficking, as well as the modulation of behavioral responses. Allosteric receptor\u2013receptor interactions in hetero-complexes give rise to concepts like meta-modulation and protein modulation. The introduction of receptor\u2013receptor interactions was the origin of the concept of meta-modulation provided by Katz and Edwards in 1999, which stood for the fine-tuning or modulation of nerve cell transmission. In 2000\u20132010, Ribeiro and Sebastiao, based on a series of papers, provided strong support for their view that adenosine can meta-modulate (fine-tune) synaptic transmission through adenosine receptors. However, another term should also be considered: protein modulation, which is the key feature of allosteric receptor\u2013receptor interactions leading to learning and consolidation by novel adapter proteins to memory. Finally, it must be underlined that allosteric receptor\u2013receptor interactions and their involvement both in brain disease and its treatment are of high interest. Their pathophysiological relevance has been obtained, especially for major depressive disorder, cocaine use disorder, and Parkinson\u2019s disease.<\/jats:p>","DOI":"10.3390\/membranes14050096","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T11:39:42Z","timestamp":1714649982000},"page":"96","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Membrane Heteroreceptor Complexes as Second-Order Protein Modulators: A Novel Integrative Mechanism through Allosteric Receptor\u2013Receptor Interactions"],"prefix":"10.3390","volume":"14","author":[{"given":"Marina","family":"Mirchandani-Duque","sequence":"first","affiliation":[{"name":"Receptomics and Brain Disorders Lab, Department of Human Physiology Physical Education and Sport, Faculty of Medicine, University of Malaga, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2070-8930","authenticated-orcid":false,"given":"Malak","family":"Choucri","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum (B0852), Solnav\u00e4gen 9, 17165 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5862-5498","authenticated-orcid":false,"given":"Juan C.","family":"Hern\u00e1ndez-Mondrag\u00f3n","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Celular, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minerva","family":"Crespo-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Celular, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalina","family":"P\u00e9rez-Olives","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, 08007 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-6414","authenticated-orcid":false,"given":"Luca","family":"Ferraro","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, Section of Medicinal and Health Products University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2549-4919","authenticated-orcid":false,"given":"Rafael","family":"Franco","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, Section of Medicinal and Health Products University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1520-4439","authenticated-orcid":false,"given":"Miguel","family":"P\u00e9rez de la Mora","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Celular, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8491-4288","authenticated-orcid":false,"given":"Kjell","family":"Fuxe","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum (B0852), Solnav\u00e4gen 9, 17165 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5736-373X","authenticated-orcid":false,"given":"Dasiel O.","family":"Borroto-Escuela","sequence":"additional","affiliation":[{"name":"Receptomics and Brain Disorders Lab, Department of Human Physiology Physical Education and Sport, Faculty of Medicine, University of Malaga, 29010 M\u00e1laga, Spain"},{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum (B0852), Solnav\u00e4gen 9, 17165 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,25]]},"reference":[{"key":"ref_1","first-page":"165","article-title":"Evidence for the Existence of Receptor Receptor Interactions in the Central Nervous-System\u2014Studies on the Regulation of Monoamine Receptors by Neuropeptides","volume":"18","author":"Fuxe","year":"1983","journal-title":"J. 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