The D1–D2 dopamine receptor heteromer is a receptor heteromer consisting of D1 and D2 protomers.
Quick Facts Dopamine receptor D1, Identifiers ...
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Quick Facts Dopamine receptor D2, Identifiers ...
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D1 and D2 receptors interact primarily through discrete amino acids in the cytoplasmic regions of each receptor, with no involvement of transmembrane parts. The intracellular loop 3 of the D2 receptor contains two adjacent arginine residues, while the carboxyl tail of the D1 receptor possesses two adjacent glutamic acid residues. The two receptors can form a heteromer complex via a salt bridge between the guanidine moiety and the carboxylic group.[1]
The signalling of the D1–D2 receptor heteromer is distinct from that of the parent receptor monomers. It comprises Gq/11 coupling, phospholipase C activation, intracellular calcium release from inositol trisphosphate receptor-sensitive stores, CaMKII activation[2] and BDNF production.[3] In comparison, signalling of the homologous D5–D2 receptor heteromer involves the influx of extracellular calcium.[4]
The D1–D2 receptor is upregulated in individuals with major depression, and especially the ratio D1–D2 to D1 receptor is markedly shifted towards the heteromer. Counteracting this upregulation decreases depressive symptoms. Disruption of the heteromer can be achieved either directly by ligands interacting with the cytoplasmic interface, less directly by ligands that target the extracellular binding site, or indirectly as a downstream effect of classical antidepressant treatment.[5] One study found negative results regarding a shift from Gs/a coupling to Gq/11 signaling; so such dynamics could be mediated by cAMP-dependent cascades rather from phospholipase C regulation.[6]
Chronic THC increased the number of D1-D2 heteromer-expressing neurons, and the number of heteromers within individual neurons in adult monkey striatum.[7]
Pei L, Li S, Wang M, Diwan M, Anisman H, Fletcher PJ, et al. (December 2010). "Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects". Nature Medicine. 16 (12): 1393–5. doi:10.1038/nm.2263. PMID 21113156. S2CID 205387382.
- Perreault ML, Fan T, Alijaniaram M, O'Dowd BF, George SR (2012). "Dopamine D1-D2 receptor heteromer in dual phenotype GABA/glutamate-coexpressing striatal medium spiny neurons: regulation of BDNF, GAD67 and VGLUT1/2". PLOS ONE. 7 (3): e33348. Bibcode:2012PLoSO...733348P. doi:10.1371/journal.pone.0033348. PMC 3299775. PMID 22428025.
- Perreault ML, Hasbi A, O'Dowd BF, George SR (2011). "The dopamine d1-d2 receptor heteromer in striatal medium spiny neurons: evidence for a third distinct neuronal pathway in Basal Ganglia". Frontiers in Neuroanatomy. 5: 31. doi:10.3389/fnana.2011.00031. PMC 3130461. PMID 21747759.
- Perreault ML, Hasbi A, Alijaniaram M, Fan T, Varghese G, Fletcher PJ, et al. (November 2010). "The dopamine D1-D2 receptor heteromer localizes in dynorphin/enkephalin neurons: increased high affinity state following amphetamine and in schizophrenia". The Journal of Biological Chemistry. 285 (47): 36625–34. doi:10.1074/jbc.M110.159954. PMC 2978591. PMID 20864528.
- Hasbi A, O'Dowd BF, George SR (June 2011). "Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance". Molecular Brain. 4: 26. doi:10.1186/1756-6606-4-26. PMC 3138392. PMID 21663703.
- George SR, O'Dowd BF (November 2007). "A novel dopamine receptor signaling unit in brain: heterooligomers of D1 and D2 dopamine receptors". TheScientificWorldJournal. 7: 58–63. doi:10.1100/tsw.2007.223. PMC 5900862. PMID 17982577.
- So CH, Verma V, O'Dowd BF, George SR (August 2007). "Desensitization of the dopamine D1 and D2 receptor hetero-oligomer mediated calcium signal by agonist occupancy of either receptor". Molecular Pharmacology. 72 (2): 450–62. doi:10.1124/mol.107.034884. PMID 17519357. S2CID 12345381.
- So CH, Varghese G, Curley KJ, Kong MM, Alijaniaram M, Ji X, et al. (September 2005). "D1 and D2 dopamine receptors form heterooligomers and cointernalize after selective activation of either receptor". Molecular Pharmacology. 68 (3): 568–78. doi:10.1124/mol.105.012229. PMID 15923381. S2CID 2565690.
- Verma V, Hasbi A, O'Dowd BF, George SR (November 2010). "Dopamine D1-D2 receptor Heteromer-mediated calcium release is desensitized by D1 receptor occupancy with or without signal activation: dual functional regulation by G protein-coupled receptor kinase 2". The Journal of Biological Chemistry. 285 (45): 35092–103. doi:10.1074/jbc.M109.088625. PMC 2966123. PMID 20807772.
- O'Dowd BF, Ji X, Alijaniaram M, Nguyen T, George SR (May 2011). "Separation and reformation of cell surface dopamine receptor oligomers visualized in cells". European Journal of Pharmacology. 658 (2–3): 74–83. doi:10.1016/j.ejphar.2011.02.030. PMID 21371461.
- Dziedzicka-Wasylewska M, Faron-Górecka A, Andrecka J, Polit A, Kuśmider M, Wasylewski Z (July 2006). "Fluorescence studies reveal heterodimerization of dopamine D1 and D2 receptors in the plasma membrane". Biochemistry. 45 (29): 8751–9. doi:10.1021/bi060702m. PMID 16846218.
- Dziedzicka-Wasylewska M, Faron-Górecka A, Górecki A, Kuśemider M (2008). "Mechanism of action of clozapine in the context of dopamine D1-D2 receptor hetero-dimerization--a working hypothesis". Pharmacological Reports. 60 (5): 581–7. PMID 19066405.
- Grymek K, Łukasiewicz S, Faron-Góreckaa A, Tworzydlo M, Polit A, Dziedzicka-Wasylewska M (2009). "Role of silent polymorphisms within the dopamine D1 receptor associated with schizophrenia on D1-D2 receptor hetero-dimerization". Pharmacological Reports. 61 (6): 1024–33. doi:10.1016/s1734-1140(09)70164-1. PMID 20081237. S2CID 4734776.
- Błasiak E, Łukasiewicz S, Szafran-Pilch K, Dziedzicka-Wasylewska M (April 2017). "Genetic variants of dopamine D2 receptor impact heterodimerization with dopamine D1 receptor". Pharmacological Reports. 69 (2): 235–241. doi:10.1016/j.pharep.2016.10.016. PMID 28119185. S2CID 11334015.
