Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS
G protein-coupled receptors (GPCRs) not only exist as monomers but also as homomers and heteromers in which allosteric receptor-receptor interactions take place, modulating the functions of the participating GPCR protomers. GPCRs can also form heteroreceptor complexes with ionotropic receptors and r...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2019.00230/full |
| _version_ | 1818287260343205888 |
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| author | Dasiel O. Borroto-Escuela Dasiel O. Borroto-Escuela Dasiel O. Borroto-Escuela Kjell Fuxe |
| author_facet | Dasiel O. Borroto-Escuela Dasiel O. Borroto-Escuela Dasiel O. Borroto-Escuela Kjell Fuxe |
| author_sort | Dasiel O. Borroto-Escuela |
| collection | DOAJ |
| description | G protein-coupled receptors (GPCRs) not only exist as monomers but also as homomers and heteromers in which allosteric receptor-receptor interactions take place, modulating the functions of the participating GPCR protomers. GPCRs can also form heteroreceptor complexes with ionotropic receptors and receptor tyrosine kinases modulating their function. Furthermore, adaptor proteins interact with receptor protomers and modulate their interactions. The state of the art is that the allosteric receptor-receptor interactions are reciprocal, highly dynamic and substantially alter the signaling, trafficking, recognition and pharmacology of the participating protomers. The pattern of changes appears to be unique for each heteromer and can favor antagonistic or facilitatory interactions or switch the G protein coupling from e.g., Gi/o to Gq or to beta-arrestin signaling. It lends a new dimension to molecular integration in the nervous system. Future direction should be aimed at determining the receptor interface involving building models of selected heterodimers. This will make design of interface-interfering peptides that specifically disrupt the heterodimer possible. This will help to determine the functional role of the allosteric receptor-receptor interactions as well as the integration of signals at the plasma membrane by the heteroreceptor complexes, vs. integration of the intracellular signaling pathways. Integration of signals also at the plasma membrane seems crucial in view of the hypothesis that learning and memory at a molecular level takes place by reorganization of homo and heteroreceptor complexes in the postsynaptic membrane. Homo and heteroreceptor complexes are in balance with each other, and their disbalance is linked to disease. Targeting heteroreceptor complexes represents a novel strategy for the treatment of brain disorders. |
| first_indexed | 2024-12-13T01:37:40Z |
| format | Article |
| id | doaj.art-2f7a93b0ad2d415790d98b30a472fb9c |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-13T01:37:40Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-2f7a93b0ad2d415790d98b30a472fb9c2022-12-22T00:03:51ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992019-09-011210.3389/fnmol.2019.00230445105Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNSDasiel O. Borroto-Escuela0Dasiel O. Borroto-Escuela1Dasiel O. Borroto-Escuela2Kjell Fuxe3Department of Neuroscience, Karolinska Institutet, Stockholm, SwedenDepartment of Biomolecular Science, Section of Physiology, University of Urbino, Campus Scientifico Enrico Mattei, Urbino, ItalyGrupo Bohío-Estudio, Observatorio Cubano de Neurociencias, Yaguajay, CubaDepartment of Neuroscience, Karolinska Institutet, Stockholm, SwedenG protein-coupled receptors (GPCRs) not only exist as monomers but also as homomers and heteromers in which allosteric receptor-receptor interactions take place, modulating the functions of the participating GPCR protomers. GPCRs can also form heteroreceptor complexes with ionotropic receptors and receptor tyrosine kinases modulating their function. Furthermore, adaptor proteins interact with receptor protomers and modulate their interactions. The state of the art is that the allosteric receptor-receptor interactions are reciprocal, highly dynamic and substantially alter the signaling, trafficking, recognition and pharmacology of the participating protomers. The pattern of changes appears to be unique for each heteromer and can favor antagonistic or facilitatory interactions or switch the G protein coupling from e.g., Gi/o to Gq or to beta-arrestin signaling. It lends a new dimension to molecular integration in the nervous system. Future direction should be aimed at determining the receptor interface involving building models of selected heterodimers. This will make design of interface-interfering peptides that specifically disrupt the heterodimer possible. This will help to determine the functional role of the allosteric receptor-receptor interactions as well as the integration of signals at the plasma membrane by the heteroreceptor complexes, vs. integration of the intracellular signaling pathways. Integration of signals also at the plasma membrane seems crucial in view of the hypothesis that learning and memory at a molecular level takes place by reorganization of homo and heteroreceptor complexes in the postsynaptic membrane. Homo and heteroreceptor complexes are in balance with each other, and their disbalance is linked to disease. Targeting heteroreceptor complexes represents a novel strategy for the treatment of brain disorders.https://www.frontiersin.org/article/10.3389/fnmol.2019.00230/fullG protein-coupled receptorheteroreceptor complexesoligomerizationbrain disordersallosteric receptor-receptor interactionsallosteric dynamic |
| spellingShingle | Dasiel O. Borroto-Escuela Dasiel O. Borroto-Escuela Dasiel O. Borroto-Escuela Kjell Fuxe Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS Frontiers in Molecular Neuroscience G protein-coupled receptor heteroreceptor complexes oligomerization brain disorders allosteric receptor-receptor interactions allosteric dynamic |
| title | Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS |
| title_full | Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS |
| title_fullStr | Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS |
| title_full_unstemmed | Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS |
| title_short | Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS |
| title_sort | oligomeric receptor complexes and their allosteric receptor receptor interactions in the plasma membrane represent a new biological principle for integration of signals in the cns |
| topic | G protein-coupled receptor heteroreceptor complexes oligomerization brain disorders allosteric receptor-receptor interactions allosteric dynamic |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2019.00230/full |
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