D1–D2 dopamine receptor heteromer

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Dopamine receptor D1
Other data
LocusChr. 5 q35.2
Dopamine receptor D2
Other data
LocusChr. 11 q22

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


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 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 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] 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]



  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. PMC 4243167. 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. name="FrederickYano2015">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. PMC 4492915. PMID 25560761.
  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