Abstract
Previously, we described the dysregulation of serotonin (5-HT) receptor subtype 5b (5-ht(5b)) in a mouse model of Rett syndrome (RTT). 5-ht(5b) has not been extensively studied, so we set out to characterize it in more detail. Unlike common cell surface receptors, 5-ht(5b) displays no membrane expression, while receptor clusters are located in endosomes. This unusual subcellular localization is at least in part controlled by glycosylation of the N-terminus, with 5-ht(5b) possessing fewer glycosylation sites than related receptors. We analyzed whether the localization to endosomes has any functional relevance and found that 5-ht(5b) receptors can specifically interact with 5-HT(1A) receptors and retain them in endosomal compartments. This interaction reduces 5-HT(1A) surface expression and is mediated by interactions between the fourth and fifth trans-membrane domain (TMD). This possibly represents a mechanism by which 5-ht(5b) receptors regulate the activity of other 5-HT receptor.