Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome

Abstract

Neurotransmitter contacts within the receptor binding site differentially contribute to the overall functional response: transmembrane helix (TM) 5 contacts promote G protein coupling whereas concerted TM5–TM6 contacts enhance β-arrestin recruitment.

A Novel “Activation Switch” Motif Common to All Aminergic Receptors

“…Interestingly, in a second D1R structure bound with dopamine (PDB 7LJD), the ligand is in a more extracellular location compared to structure 7CKZ, and the meta–OH does not interact with any TM5 serines but rather forms a H-bond with Asn 6.55 . This binding mode is consistent with a combined computational and experimental study of the D2R in which the aligned His 6.55 was also found to interact with the meta–OH of bound dopamine . Notably, both Ser 5.42 and Ser 5.46 are in different rotamers in these two structures.…”

“…This binding mode is consistent with a combined computational and experimental study of the D2R in which the aligned His 6.55 was also found to interact with the meta−OH of bound dopamine. 20 Notably, both Ser 5.42 and Ser 5.46 are in different rotamers in these two structures. If both binding modes of dopamine are feasible, then the different χ1 rotamers of TM5 serines in those two D1R active structures would argue that these serines can adopt different rotamers in the active state to accommodate the same bound agonists.…”

G protein‐coupled receptor kinase‐2 confers isoform‐specific calcium sensitivity to dopamine D 2 receptor desensitization

“…In contrast, when D 2L R was expressed instead of D 2S R, neither EGTA‐AM‐ nor BAPTA‐AM‐preincubated cells demonstrated any significant differences in desensitization compared to untreated control cells (Figure 4A,B). Desensitization of D 2S R‐mediated Kir3 responses was sensitive to BAPTA‐AM treatment also when the receptor was activated by a lower, submaximally effective 24 concentration of DA (10 nM; Figure 5).…”

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

“…Hence, the evaluation of ligand–GPCR contacts has been an important focus in several studies of signaling bias. For instance, Stepniewski et al described a common mechanism for ligand-binding contacts in aminergic receptors that are linked to (un)biased coupling responses [ 20 ]. According to their findings, ligands that establish simultaneous interactions with residues in TM5 and TM6 seem to have an unbiased coupling profile, whereas exclusive interaction with TM5 promotes G protein bias, in particular G oB .…”