Diversity and bias through receptor-receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerization
Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the recep...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2014-05-01
|
| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00071/full |
| _version_ | 1819065725391732736 |
|---|---|
| author | Kjell eFuxe Alexander O Tarakanov Wilber eRomero-Fernández Luca eFerraro Sergio eTanganelli Małgorzata eFilip Luigi Francesco Agnati Pere eGarriga Zaida eDiaz Cabiale Dasiel Oscar Borroto-Escuela |
| author_facet | Kjell eFuxe Alexander O Tarakanov Wilber eRomero-Fernández Luca eFerraro Sergio eTanganelli Małgorzata eFilip Luigi Francesco Agnati Pere eGarriga Zaida eDiaz Cabiale Dasiel Oscar Borroto-Escuela |
| author_sort | Kjell eFuxe |
| collection | DOAJ |
| description | Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the receptor protomer repertoire leading to diversity and biased recognition and signaling. In 1980ies and 1990ies it was shown that neurotensin through selective antagonistic NTR-D2likeR interactions increased the diversity of DA signalling by reducing D2R mediated dopamine signalling over D1R mediated dopamine signalling. Furthermore, D2R protomer appeared to bias the specificity of the NTR orthosteric binding site towards neuromedin N vs neurotensin in the heteroreceptor complex. Complex CCK2R-D1R-D2R interactions in possible heteroreceptor complexes were also demonstrated further increasing receptor diversity. In D2R-5-HT2AR heteroreceptor complexes the hallucinogenic 5-HT2AR agonists LSD and DOI were recently found to exert a biased agonist action on the orthosteric site of the 5-HT2AR protomer leading to the development of an active conformational state different from the one produced by 5-HT. Furthermore, as recently demonstrated allosteric A2A-D2R receptor-receptor interaction brought about not only a reduced affinity of the D2R agonist binding site but also a biased modulation of the D2R protomer signalling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced which moved away from Gi/o signaling and instead favoured b-arrestin2 mediated signalling. These examples on allosteric receptor-receptor interactions obtained over several decades serve to illustrate the significant increase in diversity and biased recognition and signaling that develop through such mechanisms. |
| first_indexed | 2024-12-21T15:51:02Z |
| format | Article |
| id | doaj.art-a9a0b053a75c4621b280f0ef871ef5e8 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-21T15:51:02Z |
| publishDate | 2014-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-a9a0b053a75c4621b280f0ef871ef5e82022-12-21T18:58:13ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922014-05-01510.3389/fendo.2014.0007182094Diversity and bias through receptor-receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerizationKjell eFuxe0Alexander O Tarakanov1Wilber eRomero-Fernández2Luca eFerraro3Sergio eTanganelli4Małgorzata eFilip5Luigi Francesco Agnati6Pere eGarriga7Zaida eDiaz Cabiale8Dasiel Oscar Borroto-Escuela9Karolinska InstitutetRussian Academy of SciencesKarolinska InstitutetUniversity of FerraraUniversity of FerraraInstitute of Pharmacology, Polish Academy of SciencesIRCCSUniversitat Politècnica de CatalunyaUniversity of MálagaKarolinska InstitutetAllosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the receptor protomer repertoire leading to diversity and biased recognition and signaling. In 1980ies and 1990ies it was shown that neurotensin through selective antagonistic NTR-D2likeR interactions increased the diversity of DA signalling by reducing D2R mediated dopamine signalling over D1R mediated dopamine signalling. Furthermore, D2R protomer appeared to bias the specificity of the NTR orthosteric binding site towards neuromedin N vs neurotensin in the heteroreceptor complex. Complex CCK2R-D1R-D2R interactions in possible heteroreceptor complexes were also demonstrated further increasing receptor diversity. In D2R-5-HT2AR heteroreceptor complexes the hallucinogenic 5-HT2AR agonists LSD and DOI were recently found to exert a biased agonist action on the orthosteric site of the 5-HT2AR protomer leading to the development of an active conformational state different from the one produced by 5-HT. Furthermore, as recently demonstrated allosteric A2A-D2R receptor-receptor interaction brought about not only a reduced affinity of the D2R agonist binding site but also a biased modulation of the D2R protomer signalling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced which moved away from Gi/o signaling and instead favoured b-arrestin2 mediated signalling. These examples on allosteric receptor-receptor interactions obtained over several decades serve to illustrate the significant increase in diversity and biased recognition and signaling that develop through such mechanisms.http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00071/fullOligomerizationreceptor-receptor interactionsDopamine receptordG protein coupled receptorheterodimerization |
| spellingShingle | Kjell eFuxe Alexander O Tarakanov Wilber eRomero-Fernández Luca eFerraro Sergio eTanganelli Małgorzata eFilip Luigi Francesco Agnati Pere eGarriga Zaida eDiaz Cabiale Dasiel Oscar Borroto-Escuela Diversity and bias through receptor-receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerization Frontiers in Endocrinology Oligomerization receptor-receptor interactions Dopamine receptor d G protein coupled receptor heterodimerization |
| title | Diversity and bias through receptor-receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerization |
| title_full | Diversity and bias through receptor-receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerization |
| title_fullStr | Diversity and bias through receptor-receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerization |
| title_full_unstemmed | Diversity and bias through receptor-receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerization |
| title_short | Diversity and bias through receptor-receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerization |
| title_sort | diversity and bias through receptor receptor interactions in gpcr heteroreceptor complexes focus on examples from dopamine d2 receptor heteromerization |
| topic | Oligomerization receptor-receptor interactions Dopamine receptor d G protein coupled receptor heterodimerization |
| url | http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00071/full |
| work_keys_str_mv | AT kjellefuxe diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization AT alexanderotarakanov diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization AT wilbereromerofernandez diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization AT lucaeferraro diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization AT sergioetanganelli diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization AT małgorzataefilip diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization AT luigifrancescoagnati diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization AT pereegarriga diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization AT zaidaediazcabiale diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization AT dasieloscarborrotoescuela diversityandbiasthroughreceptorreceptorinteractionsingpcrheteroreceptorcomplexesfocusonexamplesfromdopamined2receptorheteromerization |