Ass.Prof. Dr. Jana Haase
School of Biomolecular and Biomedical Sciences
UCD Conway Institute
University College Dublin
Programm
“Serotonin transporter regulation by Gα proteins: evidence for coupling of serotonin transport and the G protein cycle”
The serotonin transporter (SERT) mediates Na+-dependent, high-affinity uptake of serotonin (5-hydroxytryptamine, 5HT) into serotoninergic neurons and plays a key role in fine-tuning serotonin dependent signalling in the brain. Among the proteins we have identified to interact with the transporter and potentially regulate its activity are subunits of heterotrimeric G proteins, including Gαq, Gαi1, and Gαi2. In an initial study, we have recently shown that the lack of Gαq in knockout mice causes a sex specific upregulation of SERT activity in distinct brain regions paralleled by changes in tissue 5HT levels and Gαi1 protein expression (Haase et al, 2021). Subsequently, we accumulated evidence for a novel and previously unknown mechanism by which SERT activity is regulated by Gα proteins. Corroborating our findings from Gαq knockout mice, we showed that the transporter turnover rate is substantially enhanced in CRISPR Gα knockout HEK cells, an effect that can be reversed by co-expression of Gαq. We also observed altered ion dependence and uptake inhibition potency by escitalopram in Gα knockout cells. SERT activity modulation by Gαq mutants and pharmacological inhibition in mouse brain synaptosomes and transfected mammalian cells lead us to propose a model for the coupling between serotonin transport and the G protein cycle. Our model suggests that SERT may be able to activate Gα proteins in a GPCR-like manner and subsequently relies on the completion of the G protein cycle for progression of the transport cycle.
Host: Oliver KUDLACEK
Contact for questions: Helmut KUBISTA