Dopamine D4 receptor oligomerization – contribution to receptor biogenesis
Abstract
Dopamine D 4 receptors (D 4 Rs) are G protein‐coupled receptors that play a role in attention and cognition. In the present study, we investigated the dimerization properties of this receptor. Western blot analysis of the human D 4.2 R, D 4.4 R and D 4.7 R revealed the presence of higher molecular weight immunoreactive bands, which might indicate the formation of receptor dimers and multimers. Homo‐ and heterodimerization of the receptors was confirmed by co‐immunoprecipitation and bioluminescence resonance energy transfer studies. Although dimerization of a large number of G protein‐coupled receptors has been described, the functional importance often remains to be elucidated. Folding efficiency is rate‐limiting for D 4 R biogenesis and quality control in the endoplasmic reticulum plays an important role for D 4 R maturation. Co‐immunoprecipitation and immunofluorescence microscopy studies using wild‐type and a nonfunctional D 4.4 R folding mutant show that oligomerization occurs in the endoplasmic reticulum and that this plays a role in the biogenesis and cell surface targeting of the D 4 R. The different polymorphic repeat variants of the D 4 R display differential sensitivity to the chaperone effect. In the present study, we show that this is also reflected by bioluminescence resonance energy transfer saturation assays, suggesting that the polymorphic repeat variants have different relative affinities to form homo‐ and heterodimers. In summary, we conclude that D 4 Rs form oligomers with different affinities and that dimerization plays a role in receptor biogenesis. Structured digital abstract D4.4R physically interacts with D4.2R by anti tag coimmunoprecipitation (View interaction) D4.xR physically interacts with D4.4R by anti tag coimmunoprecipitation (View interaction) D4.xR and D4.xR physically interact by bioluminescence resonance energy transfer (View interaction)
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Functional significance of the DRD4 48-bp exon III VNTR polymorphism has been demonstrated.
“Functional significance of this polymorphism has been demonstrated [70–75].”
From Genetics of child aggression, a systematic review (2024) · cites this paper as [75]
Cites
Rocheville, M., Lange, D. C., Kumar, U., Patel, S. C., Patel, R. C., & Patel, Y. (2000) · Science · doi:10.1126/science.288.5463.154 · Cited by 887 · see citing works
A Trafficking Checkpoint Controls GABAB Receptor Heterodimerization
Margeta, M., Jan, Y. N., & Jan, L. Y. (2000) · Neuron · doi:10.1016/s0896-6273(00)00012-x · Cited by 680 · see citing works
Hillion, J., Canals, M., Torvinen, M., Casadó, V., Scott, R. P., Terasmaa, A., Hansson, A. C., Watson, S. J., Olah, M. E., Mallol, J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m107731200 · Cited by 499 · see citing works
Rashid, A. J., So, C. H., Kong, M. M. C., Furtak, T., El-Ghundi, M., Cheng, R., O’Dowd, B. F., & George, S. R. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604049104 · Cited by 492 · see citing works
Mercier, J.-F., Salahpour, A., Angers, S., Breit, A., & Bouvier, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205767200 · Cited by 474 · see citing works
Adenosine A2A-Dopamine D2 Receptor-Receptor Heteromerization
Canals, M., Marcellino, D. J., Fanelli, F., Ciruela, F., de Benedetti, P., Goldberg, S. R., Neve, K. A., Fuxé, K., Agnati, L. F., Woods, A. S., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306451200 · Cited by 432 · see citing works
Self-citationAizman, O., Brismar, H., Uhlén, P., Zettergren-Markus, E., Levey, A. I., Forssberg, H., Greengard, P., & Aperia, A. C. (2000) · Nature Neuroscience · doi:10.1038/72929 · Cited by 415 · see citing works
Galvez, T., Duthey, B., Kniazeff, J., Blahoš, J., Rovelli, G., Bettler, B., Prézeau, L., & Pin, J. (2001) · The EMBO Journal · doi:10.1093/emboj/20.9.2152 · Cited by 383 · see citing works
Kearn, C. S., Blake-Palmer, K. G., Daniel, E., Mackie, K., & Glass, M. (2005) · Molecular Pharmacology · doi:10.1124/mol.104.006882 · Cited by 358 · see citing works
Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation
Han, Y., Moreira, I. S., Urizar, E., Weinstein, H., & Javitch, J. A. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.199 · Cited by 339 · see citing works
G protein‐coupled receptor hetero‐dimerization: contribution to pharmacology and function
Milligan, G. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00169.x · Cited by 326 · see citing works
Homodimerization of the β2-Adrenergic Receptor as a Prerequisite for Cell Surface Targeting
Salahpour, A., Angers, S., Mercier, J.-F., Lagacé, M., Marullo, S., & Bouvier, M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403363200 · Cited by 297 · see citing works
Detection of heteromerization of more than two proteins by sequential BRET-FRET
Carriba, P., Navarro, G., Ciruela, F., Ferré, S., Casadó, V., Agnati, L. F., Cortés, A., Mallol, J., Fuxé, K., Canela, E. I., et al. (2008) · Nature Methods · doi:10.1038/nmeth.1229 · Cited by 281 · see citing works
Self-citationCabello, N., Gandía, J., Bertarelli, D. C. G., Watanabe, M., Lluı́s, C., Franco, R., Ferré, S., Luján, R., & Ciruela, F. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06078.x · Cited by 253 · see citing works
Self-citationIdentification of Dopamine D1–D3 Receptor Heteromers
Marcellino, D. J., Ferré, S., Casadó, V., Cortés, A., Foll, B. L., Mazzola, C., Drago, F., Saur, O., Stark, H., Soriano, A., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710349200 · Cited by 232 · see citing works
D2/D3 Dopamine Receptor Heterodimers Exhibit Unique Functional Properties
Scarselli, M., Novi, F., Schallmach, E., Lin, R., Baragli, A., Colzi, A., Griffon, N., Corsini, G. U., Sokoloff, P., Levenson, R. G., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102297200 · Cited by 214 · see citing works
Analysis of receptor oligomerization by FRAP microscopy
Dorsch, S., Klotz, K., Engelhardt, S. H., Lohse, M. J., & Bünemann, M. (2009) · Nature Methods · doi:10.1038/nmeth.1304 · Cited by 211 · see citing works
Evolution and cell biology of dopamine receptors in vertebrates
Callier, S., Snapyan, M., Crom, S. L., Prou, D., Vincent, J., & Vernier, P. (2003) · Biology of the Cell · doi:10.1016/s0248-4900(03)00089-3 · Cited by 210 · see citing works
Reciprocal Regulation of Dopamine D1 and D3 Receptor Function and Trafficking by Heterodimerization
Fiorentini, C., Busi, C., Gorruso, E., Gotti, C., Spano, P., & Missale, C. (2008) · Molecular Pharmacology · doi:10.1124/mol.107.043885 · Cited by 209 · see citing works
Schmauss, C., Haroutunian, V. H., Davis, K. L., et al. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.19.8942 · Cited by 165 · see citing works
Marcellino, D. J., Carriba, P., Filip, M., Borgkvist, A., Frankowska, M., Bellido-Estévez, I., Tanganelli, S., Müller, C. E., Fisone, G., Lluı́s, C., et al. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.12.011 · Cited by 164 · see citing works
Karpa, K. D., Lin, R., Kabbani, N., et al. (2000) · Molecular Pharmacology · doi:10.1124/mol.58.4.677 · Cited by 155 · see citing works
The dopamine D4 receptor: biochemical and signalling properties
Rondou, P., Haegeman, G., & Craenenbroeck, K. V. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0293-y · Cited by 132 · see citing works
Self-citationHeterooligomerization of human dopamine receptor 2 and somatostatin receptor 2
Baragli, A., Alturaihi, H., Watt, H. L., Abdallah, A., & Kumar, U. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.07.007 · Cited by 128 · see citing works
Dopamine D2 receptor dimers in human and rat brain
Zawarynski, P., Tallerico, T., Seeman, P. M., Lee, S. P., O’Dowd, B. F., & George, S. R. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)01588-9 · Cited by 123 · see citing works
Navarro, G., Carriba, P., Gandía, J., Ciruela, F., Casadó, V., Cortés, A., Mallol, J., Canela, E. I., Lluís, C., & Franco, R. (2008) · The Scientific World JOURNAL · doi:10.1100/tsw.2008.136 · Cited by 121 · see citing works
Self-citationSo, C. H., Varghese, G. K., Curley, K. J., Kong, M. M. C., Alijaniaram, M., Ji, X., Nguyen, T., O’Dowd, B. F., & George, S. R. (2005) · Molecular Pharmacology · doi:10.1124/mol.105.012229 · Cited by 116 · see citing works
Folding Efficiency Is Rate-limiting in Dopamine D4 Receptor Biogenesis
Van Craenenbroeck, K., Clark, S. D., Cox, M. J., Oak, J. N., Liu, F., & Van Tol, H. H. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414043200 · Cited by 107 · see citing works
Instability of a Class A G Protein-Coupled Receptor Oligomer Interface
Fonseca, J. M., & Lambert, N. A. (2009) · Molecular Pharmacology · doi:10.1124/mol.108.053876 · Cited by 89 · see citing works
Wang, M., Pei, L., Fletcher, P. J., Kapur, S., Seeman, P. M., & Liu, F. (2010) · Molecular Brain · doi:10.1186/1756-6606-3-25 · Cited by 87 · see citing works
BTB Protein KLHL12 Targets the Dopamine D4 Receptor for Ubiquitination by a Cul3-based E3 Ligase
Rondou, P., Haegeman, G., Vanhoenacker, P., & Craenenbroeck, K. V. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708473200 · Cited by 80 · see citing works
Self-citationDopamine D2–D3 receptor heteromers: pharmacological properties and therapeutic significance
Maggio, R., & Millan, M. J. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.10.001 · Cited by 73 · see citing works
A Novel Dopamine Receptor Signaling Unit in Brain: Heterooligomers of D1 And D2 Dopamine Receptors
George, S. R., & O’Dowd, B. F. (2007) · The Scientific World JOURNAL · doi:10.1100/tsw.2007.223 · Cited by 53 · see citing works
van Craenenbroeck, K., Vanhoenacker, P., Leysen, J., & Haegeman, G. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01719.x · Cited by 39 · see citing works
Self-citationResistance of the dopamine D4 receptor to agonist-induced internalization and degradation
Spooren, A., Rondou, P., Debowska, K., Lintermans, B., Vermeulen, L., Samyn, B., Skieterska, K., Debyser, G., Devreese, B. V., Vanhoenacker, P., et al. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2009.11.013 · Cited by 32 · see citing works
Self-citationBorroto‐Escuela, D. O., García-Negredo, G., Garriga, P., Fuxé, K., & Ciruela, F. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.04.002 · Cited by 31 · see citing works
Self-citationOligomers of D2 Dopamine Receptors: Evidence From Ligand Binding
Strange, P. G. (2005) · Journal of Molecular Neuroscience · doi:10.1385/jmn:26:2-3:155 · Cited by 23 · see citing works
Influence of the antipsychotic drug pipamperone on the expression of the dopamine D4 receptor
Craenenbroeck, K. V., Gellynck, E., Lintermans, B., Leysen, J. E., Tol, H. H. M. V., Haegeman, G., & Vanhoenacker, P. (2006) · Life Sciences · doi:10.1016/j.lfs.2006.08.024 · Cited by 17 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Genetics of Human Social Behavior
Ebstein, R. P., Israel, S., Chew, S. H., Zhong, S., & Knafo, A. (2010) · Neuron · doi:10.1016/j.neuron.2010.02.020 · Cited by 323 · see citing works
An update on the physiological and therapeutic relevance of GPCR oligomers
Farran, B. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.01.008 · Cited by 115 · see citing works
Genetics of child aggression, a systematic review
Koyama, E., Kant, T., Takata, A., Kennedy, J. L., & Zai, C. C. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02870-7 · Cited by 33 · see citing works
GPCR Oligomerization: Contribution to Receptor Biogenesis
Van Craenenbroeck, K. (2012) · Subcellular Biochemistry · doi:10.1007/978-94-007-4765-4_3 · Cited by 18 · see citing works
- Authors
- Van Craenenbroeck, K., Borroto‐Escuela, D. O., Romero‐Fernandez, W., Skieterska, K., Rondou, P., Lintermans, B., Vanhoenacker, P., Fuxe, K., Ciruela, F., & Haegeman, G.
- Affiliations
- Karolinska Institutet (SE)
- Ghent University Hospital (BE)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2011-03-10
- Volume
- 278
- Issue
- 8
- Pages
- 1333-1344
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- OpenAlex
- W1649187440
- Cited by
- 33
- References
- 38
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 4 · 2015: 3 · 2014: 7 · 2013: 6 · 2012: 3
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Vetenskapsrådet (04X-715)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopamine D4 receptor, receptor oligomerization, receptor dimerization, receptor biogenesis, cell surface targeting, G protein-coupled receptors, homo- and heterodimers
- MeSH terms
- Endoplasmic Reticulum, Humans, Luminescent Measurements, Protein Folding, Dimerization, Receptors, Dopamine D4, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
