Biased signalling and heteromization of the Dopamine D2 receptor in Schizophrenia and Parkinson's disease

Biased signalling and heteromization of the Dopamine D2 receptor in Schizophrenia and Parkinson’sdisease As a significant component of dopamine signalling in the brain, the dopamine D2 receptor(D2R), a member of the Class A GPCR family, is an important target in the treatment of neurologicalconditions such as schizophrenia and Parkinson’s disease. D2R shows a variety of signalling pathwaysthrough G proteins, including adenylyl cyclase inhibition, Gbgpotentiation of adenylyl cyclase 2, andERK kinase activation, in addition tob-arrestin recruitment,. These pathways are differentially activatedby some agonists and it has been suggested that D2R ligands with Gai/o antagonist andb-arrestinagonist activity may have anti-psychotic behavioural activity with reduced extra-pyramidal side effects.D2R has also been found to form homodimers or higher-order hetero-oligomers with other GPCRs,which may modulate D2R conformation and activity, thus constituting an additional form of allostericreceptor regulation. Based on these findings, we have computationally modelled the full-length struc-ture of D2R, including its long intracellular loop 3 (ICL3) that is 1301residues in length and absent inall homologous GPCR crystal structures. Using state-of-the-art tools, such as ROSETTA for ab initio pro-tein folding and ACEMD for micro-second1molecular dynamics (MD) simulations we have successfullyde novo folded ICL3, which primarily consists of extensions to transmembrane helices (TMH) 5 and 6and an intervening disordered histidine/proline-rich region, which is highly flexible. The latter isobserved to interact with other receptor intracellular loops (ICL1 and ICL2) and appears to restrictaccess to the G-protein binding-site. In addition, we have docked a structurally diverse collection of 14ligands (biased agonists, antagonists and allosteric modulators) into our D2R model and observed char-acteristic binding patterns suggestive of different biased signalling mechanisms. Finally, throughprotein-protein docking with ROSETTADOCK, we have generated a complete heterodimer model ofD2R with the Adenosine A2A receptor (AA2AR), where a mutual interface is formed between theirrespective TMHs 4 and 5, as well as an association between the C-terminus of AA2AR and ICL3 of D2R.This may be a particularly relevant biological complex in the treatment of Parkinson’s disease whereantagonists of AA2AR have been shown to ameliorate disease effects, potentially through direct interac-tion with D2R.