Lectures and seminars Fysiologförening’s seminar by Dr. Benita Sjögren

23-08-2024 1:15 pm Add to iCal
Campus Solna Nils Ringertz, Biomedicum

Warm welcome to this semester’s first Fysiologförening’s seminar by Dr. Benita Sjögren, Assistant Professor at UC Irvine. Mechanisms of Regulator of G Protein Signaling (RGS) protein regulation – from biology to drug discovery.

Mechanisms of Regulator of G Protein Signaling (RGS) protein regulation – from biology to drug discovery.

Regulator of G protein Signaling (RGS) proteinsreduce duration and amplitude of signaling through G proteincoupled receptors (GPCRs) by binding to, and accelerating GTP hydrolysis on, active Gα subunits of heterotrimeric G proteins. The majority of RGS proteins also possess additional functions not related to their canonical effect. 

Since their discovery in the mid-1990’s, RGS proteins have emerged as potential novel drug targets in numerous disease states. However, with a lack of enzymatic activity or sites amenable to small molecule binding, RGS proteins are difficult to target. We showed that increasing RGS protein levels results in increased function both in vitro and in vivo. Thus, our work is focused on deciphering the mechanisms regulating RGS protein levels and function and applying the knowledge of these mechanisms to inform drug discovery efforts. RGS proteins are tightly regulated in time and space and expression is often altered during pathogenesis. The precise mechanisms involved in regulation are distinct for each member of the RGS protein family. Current work in the lab is mainly focused on two members, RGS2 and RGS10. Low levels of RGS2 are implicated in several pathologies, including hypertension, heart failure and asthma, all associated with augmented Gαq signaling. RGS2 is a selective modulator of Gαq and increasing RGS2 protein levels would therefore have broad clinical implications. RGS2 is rapidly degraded through the ubiquitin-proteasomal pathway. Our work aims to dissect the precise molecular mechanisms driving RGS2 protein degradation, and to develop screening strategies to identify small molecule RGS2 stabilizers. 

RGS10 has emerged as a promising target in neuroinflammatory diseases, such as Parkinson’s and Alzheimer’s Disease. RGS10 is highly expressed in microglia, where it suppresses pro-inflammatory signaling. Furthermore, it is transcriptionally silenced following microglial activation. As such, modulating RGS10 expression is a promising strategy to suppress pro-inflammatory microglial activation. However, no chemical tools with this ability currently exist and the mechanisms by which RGS10 modulates microglial activation states are largely unknown. Our work aims to decipher these mechanisms through bioinformatic approaches. We have also employed a phenotypic high-throughput assay to screen for compounds with the ability to reverse RGS10 silencing.

Contact

Johanna Lanner Senior Lecturer