{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T18:57:09Z","timestamp":1791140229700,"version":"4.1.0"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2017,8,22]],"date-time":"2017-08-22T00:00:00Z","timestamp":1503360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/501100002706","name":"AFA F\u00f6rs\u00e4kring","doi-asserted-by":"publisher","award":["130328"],"award-info":[{"award-number":["130328"]}],"id":[{"id":"10.13039\/501100002706","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003792","name":"Hj\u00e4rnfonden","doi-asserted-by":"publisher","award":["FO2016-0302"],"award-info":[{"award-number":["FO2016-0302"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006310","name":"Medicinska Forskningsr\u00e5det","doi-asserted-by":"publisher","award":["04X-715"],"award-info":[{"award-number":["04X-715"]}],"id":[{"id":"10.13039\/501100006310","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Studies on serotonin-selective reuptake inhibitors have established that disturbances in the ascending 5-HT neuron systems and their 5-HT receptor subtypes and collateral networks to the forebrain contribute to the etiology of major depression and are targets for treatment. The therapeutic action of serotonin-selective reuptake inhibitors is of proven effectiveness, but the mechanisms underlying their effect are still unclear. There are many 5-HT subtypes involved; some need to be blocked (e.g., 5-HT2A, 5-HT3, and 5-HT7), whereas others need to be activated (e.g., postjunctional 5-HT1A and 5-HT4). These state-of-the-art developments are in line with the hypothesis that the development of major depression can involve an imbalance of the activity between different types of 5-HT isoreceptors. In the current study, using in situ proximity ligation assay (PLA), we report evidence for the existence of brain 5-HT1A\u20135-HT2A isoreceptor complexes validated in cellular models with bioluminescence resonance energy transfer (BRET2) assay. A high density of PLA-positive clusters visualizing 5-HT1A\u20135-HT2A isoreceptor complexes was demonstrated in the pyramidal cell layer of the CA1\u2013CA3 regions of the dorsal hippocampus. A marked reduction in the density of PLA-positive clusters was observed in the CA1 and CA2 regions 24 h after a forced swim test session, indicating the dynamics of this 5-HT isoreceptor complex. Using a bioinformatic approach, previous work indicates that receptors forming heterodimers demonstrate triplet amino acid homologies. The receptor interface of the 5-HT1A\u20135-HT2A isoreceptor dimer was shown to contain the LLG and QNA protriplets in the transmembrane and intracellular domain, respectively. The 5-HT2A agonist TCB2 markedly reduced the affinity of the 5-HT1A agonist ipsapirone for the 5-HT1A agonist binding sites in the frontal lobe using the 5-HT1A radioligand binding assay. This action was blocked by the 5-HT2A antagonist ketanserin. It is proposed that the demonstrated 5-HT1A\u20135-HT2A isoreceptor complexes may play a role in depression through integration of 5-HT recognition, signaling and trafficking in the plasma membrane in two major 5-HT receptor subtypes known to be involved in depression. Antagonistic allosteric receptor\u2013receptor interactions appear to be involved in this integrative process.<\/jats:p>","DOI":"10.1021\/acsomega.7b00629","type":"journal-article","created":{"date-parts":[[2017,8,22]],"date-time":"2017-08-22T07:16:15Z","timestamp":1503386175000},"page":"4779-4789","source":"Crossref","is-referenced-by-count":62,"title":["Existence of Brain 5-HT1A\u20135-HT2A Isoreceptor Complexes with Antagonistic Allosteric Receptor\u2013Receptor Interactions Regulating 5-HT1A Receptor Recognition"],"prefix":"10.1021","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5736-373X","authenticated-orcid":true,"given":"Dasiel O.","family":"Borroto-Escuela","sequence":"first","affiliation":[{"name":"Karolinska Institutet , , ,","place":["Stockholm, Sweden, 17177"]},{"name":"Grupo Bohi\u0301o-Estudio , , Zayas 50 , ,","place":["Yaguajay, Cuba, 62100"]},{"name":"University of Urbino, Campus Scientifico Enrico Mattei , , via Ca\u2019 le Suore 2 , ,","place":["Urbino, Italy, I-61029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Karolinska Institutet , , ,","place":["Stockholm, Sweden, 17177"]},{"name":"Jilin University , , Qianjin Street No. 2699 , ,","place":["Changchun, China, 130012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander O.","family":"Tarakanov","sequence":"additional","affiliation":[{"name":"St. Petersburg Institute for Informatics and Automation , , ,","place":["Saint Petersburg, Russia, 199178"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Savelli","sequence":"additional","affiliation":[{"name":"Karolinska Institutet , , ,","place":["Stockholm, Sweden, 17177"]},{"name":"University of Urbino, Campus Scientifico Enrico Mattei , , via Ca\u2019 le Suore 2 , ,","place":["Urbino, Italy, I-61029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Narva\u0301ez","sequence":"additional","affiliation":[{"name":"Universidad de Ma\u0301laga , , Campus de Teatinos s\/n , ,","place":["Ma\u0301laga, Espan\u0303a, 29071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirill","family":"Shumilov","sequence":"additional","affiliation":[{"name":"Universidad de Ma\u0301laga , , Campus de Teatinos s\/n , ,","place":["Ma\u0301laga, Espan\u0303a, 29071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuniesky","family":"Andrade-Talavera","sequence":"additional","affiliation":[{"name":"Karolinska Institutet , , ,","place":["Stockholm, Sweden, 17177"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Jimenez-Beristain","sequence":"additional","affiliation":[{"name":"Karolinska Institutet , , Von Eulers va\u0308g 8 , ,","place":["Stockholm, Sweden, 17177"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartosz","family":"Pomierny","sequence":"additional","affiliation":[{"name":"Karolinska Institutet , , ,","place":["Stockholm, Sweden, 17177"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaida","family":"Di\u0301az-Cabiale","sequence":"additional","affiliation":[{"name":"Universidad de Ma\u0301laga , , Campus de Teatinos s\/n , ,","place":["Ma\u0301laga, Espan\u0303a, 29071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Cuppini","sequence":"additional","affiliation":[{"name":"University of Urbino, Campus Scientifico Enrico Mattei , , via Ca\u2019 le Suore 2 , ,","place":["Urbino, Italy, I-61029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Ambrogini","sequence":"additional","affiliation":[{"name":"University of Urbino, Campus Scientifico Enrico Mattei , , via Ca\u2019 le Suore 2 , ,","place":["Urbino, Italy, I-61029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Lindskog","sequence":"additional","affiliation":[{"name":"Karolinska Institutet , , ,","place":["Stockholm, Sweden, 17177"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjell","family":"Fuxe","sequence":"additional","affiliation":[{"name":"Karolinska Institutet , , ,","place":["Stockholm, Sweden, 17177"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2017,8,22]]},"reference":[{"key":"2026090209123965700_cit1","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.pharmthera.2012.09.006","article-title":"Serotonin receptors involved in antidepressant\neffects","volume":"137","author":"Artigas","year":"2013","journal-title":"Pharmacol. 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