D1–D2 dopamine receptor heteromer

Dopamine receptor D1
Identifiers
Symbol	DRD1
Entrez	1812
HUGO	3020
OMIM	126449
RefSeq	NP_000785
UniProt	P21728
Other data
Locus	Chr. 5 q35.2

Dopamine receptor D2
Identifiers
Symbol	DRD2
Entrez	1813
HUGO	3023
OMIM	126450
RefSeq	NP_000786
UniProt	P14416
Other data
Locus	Chr. 11 q22

The D₁–D₂ dopamine receptor heteromer is a receptor heteromer consisting of D₁ and D₂ protomers.

Structure

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]

Signal transduction

The signalling of the D₁–D₂ receptor heteromer is distinct from that of the parent receptor monomers. It comprises G_q/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]

Physiology

The D₁–D₂ receptor is upregulated in individuals suffering from 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][6]

Ligands

• SKF-83,959^[7]

References

1. O'Dowd BF, Ji X, Nguyen T, George SR (Jan 2012). "Two amino acids in each of D1 and D2 dopamine receptor cytoplasmic regions are involved in D1-D2 heteromer formation". Biochemical and Biophysical Research Communications. 417 (1): 23–8. doi:10.1016/j.bbrc.2011.11.027. PMID 22100647.
2. Ng J, Rashid AJ, So CH, O'Dowd BF, George SR (Jan 2010). "Activation of calcium/calmodulin-dependent protein kinase IIalpha in the striatum by the heteromeric D1-D2 dopamine receptor complex". Neuroscience. 165 (2): 535–41. doi:10.1016/j.neuroscience.2009.10.017. PMC 2814448. PMID 19837142.
3. Hasbi A, Fan T, Alijaniaram M, Nguyen T, Perreault ML, O'Dowd BF, George SR (Dec 2009). "Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth". Proceedings of the National Academy of Sciences of the United States of America. 106 (50): 21377–82. doi:10.1073/pnas.0903676106. PMC 2795506. PMID 19948956.
4. Hasbi A, O'Dowd BF, George SR (Feb 2010). "Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms". Current Opinion in Pharmacology. 10 (1): 93–9. doi:10.1016/j.coph.2009.09.011. PMC 2818238. PMID 19897420.
5. Pei L, Li S, Wang M, Diwan M, Anisman H, Fletcher PJ, Nobrega JN, Liu F (Dec 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.
6. Frederick, A L; Yano, H; Trifilieff, P; Vishwasrao, H D; Biezonski, D; Mészáros, J; Urizar, E; Sibley, D R; Kellendonk, C; Sonntag, K C; Graham, D L; Colbran, R J; Stanwood, G D; Javitch, J A (2015). "Evidence against dopamine D1/D2 receptor heteromers". Molecular Psychiatry. 20 (11): 1373–1385. doi:10.1038/mp.2014.166. ISSN 1359-4184.
7. Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O'Dowd BF, George SR (Jan 2007). "D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum". Proceedings of the National Academy of Sciences of the United States of America. 104 (2): 654–9. doi:10.1073/pnas.0604049104. PMC 1766439. PMID 17194762.

Further reading

• 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. 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, Seeman P, O'Dowd BF, George SR (Nov 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 (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 (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. PMID 17982577.
• So CH, Verma V, O'Dowd BF, George SR (Aug 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.
• So CH, Varghese G, Curley KJ, Kong MM, Alijaniaram M, Ji X, Nguyen T, O'dowd BF, George SR (Sep 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.
• Verma V, Hasbi A, O'Dowd BF, George SR (Nov 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 (Jul 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.