G-protein coupled receptors & autism -- reflections on a double-edged sword at the example of the oxytocin receptor system.

ABSTRACT

G-protein coupled receptors (GPCR) tend to desensitize/internalize when exposed to excess agonist.Previously, we have supported the argument that in the case of the oxytocin receptor (OTR), excess agonist (oxytocin, OT) at birth could be implicated with behavioural disorders of the autistic spectrum. In this review, more recent evidence for this hypothesis is summarized, and it is juxtaposed against reports where exogenous OT was found beneficial in alleviating certain undesired behaviours. Facing this dichotomy, we suggest possible in silico drug discovery approaches to mitigate undesired side effect of OT administration/OTR desensitization, especially in the light of potentially emerging agonist therapies. For this, the most important structural features of OTR are reviewed, and we highlight here the need for higher level of theory studies at the easier approachable extracellular receptor side, where loop 3(e3) and the N-terminated strain of OTR appear to offer targets of particular interest for the development of an agent that conditions the action of excess OT. Another approach, based on the development of new agonists with an improved receptor activation to receptor phosphorylation ratio, is also discussed. Finally, the issue of OTR desensitization is put into the broader context of GPCR desensitization and possible implications for behavioural disorders, and the case is made for the usefulness of computational studies in this area.