The differential signalling of the succinate receptor SUCNR1/GPR91, through Gi versus Gq
(2022) KMBM05 20221Applied Microbiology
- Abstract
- G protein-coupled receptors are the biggest family of membrane bound receptor in the human genome, they are also target for many drugs due to their accessible location in the cell membrane. We have characterized the G protein recruitment of the succinate receptor 1 (SUCNR1/GPR91). GPR91 was deorphanized in 2004 and already then it was suggested that GPR91 could couple to the Gi-family and the Gq-family of G proteins. Since then, the fact that it could do this have been debated. We have used and optimized the TRUPATH biosensor (Olsen et al., 2020) to show dose-response recruitment curves for both hGPR91 and mGPR91 for the Gi- and Gq-family of G proteins. We show that hGPR91 recruits all tested α-subunits of the Gi- and Gq-family whilst... (More)
- G protein-coupled receptors are the biggest family of membrane bound receptor in the human genome, they are also target for many drugs due to their accessible location in the cell membrane. We have characterized the G protein recruitment of the succinate receptor 1 (SUCNR1/GPR91). GPR91 was deorphanized in 2004 and already then it was suggested that GPR91 could couple to the Gi-family and the Gq-family of G proteins. Since then, the fact that it could do this have been debated. We have used and optimized the TRUPATH biosensor (Olsen et al., 2020) to show dose-response recruitment curves for both hGPR91 and mGPR91 for the Gi- and Gq-family of G proteins. We show that hGPR91 recruits all tested α-subunits of the Gi- and Gq-family whilst mGPR91 recruits all except for αQ. We also show that mGPR91 is approximately 1 order more potent than hGPR91. We conclude that the TRUPATH biosensor is a good tool for investigation of G protein recruitment, but it needs to be optimized to fit each receptor that should be investigated. Further on we suggest using the results obtained as a guide for further investigation of GPR91 structurally as well as to see if there is any bias signalling occurring. (Less)
- Popular Abstract
- Better and safer drugs, the importance of understanding how cells talk
Key ingredients when trying to understand how and why a disease progresses and when eventually finding a treatment or drug is to understand WHAT is happening in the diseased cells and WHY it is happening. Many diseases are a result of signalling within or between cells going wrong. To be able to effectively address the problem one needs to know as much as there is about the root cause. In this thesis its shown that one specific cell-signal-mediator (receptor) can signal in two very different ways, with the same signal-molecule (ligand) that could lead to two separate outcomes.
G protein-coupled receptors (GPCRs) are one of the most common mediators of signalling... (More) - Better and safer drugs, the importance of understanding how cells talk
Key ingredients when trying to understand how and why a disease progresses and when eventually finding a treatment or drug is to understand WHAT is happening in the diseased cells and WHY it is happening. Many diseases are a result of signalling within or between cells going wrong. To be able to effectively address the problem one needs to know as much as there is about the root cause. In this thesis its shown that one specific cell-signal-mediator (receptor) can signal in two very different ways, with the same signal-molecule (ligand) that could lead to two separate outcomes.
G protein-coupled receptors (GPCRs) are one of the most common mediators of signalling in cells being involved in everything from hormone and immune signalling to being central parts of our vision, olfaction, and taste. GPCRs are also one of the most common targets for drugs. GPCRs are dependent on G proteins to bind to them on the inside of the cell and are the ones that further signals in the cell. For the G-protein to bind to the GPCR it must be called upon from the outside of the cell by a signal molecule. There are four main types of G proteins that can bind to the receptor, resulting in 4 different signal ways. We have shown that the succinate receptor 1 (SUCNR1/GPR91) that is one of the approximately 800 GPCRs we have in our cells, is able to bind two different types of G proteins (called Gi and Gq), which as mentioned, eventually can lead to different cellular outcomes. We also show that GPR91 binds more consistently and more strongly to one (Gi) over the other (Gq). The reason for the receptor’s preference towards Gi is not entirely known, but we do know that Gi and Gq have differences to their structures, which would affect how and how strongly it can bind to the receptor. We also compared the succinate receptor from mouse with the one from human. Here we observed that the mouse-receptor needed, in general, less signal molecules to call the two different G proteins than what the human-receptor needed. Why this is, is also not known, but as for the different G proteins, the mouse and human receptor have structural differences that could affect how it binds the signal molecule and then how it interacts with the G protein. So again, why is this knowledge important? Giving the example of the investigated succinate receptor (GPR91) we know that it takes part in signalling in many different tissues (e.g., liver, brain, heart, and kidney) and are involved in different diseases in these tissues. So, if we can predict and control the behaviour of GPCRs that as mentioned are very common drug targets, we can design more precise and efficacious drugs that in the end will also result in less side effects which is very desirable. How do we now move forward with this knowledge? Now that we know that GPR91 can signal with two different G proteins we want to know what is controlling the behaviour. Can we find a signal molecule that affects GPR91 to choose one signal way over the other? Can we attribute a signal way to specific locations in the body? These are questions to be answered in the future. And the answers will lead drug discovery and development forward. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9091536
- author
- Liljewall, Sofie LU
- supervisor
- organization
- course
- KMBM05 20221
- year
- 2022
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- GPR91, SUCNR1, G protein recruitment, Gi, Gq, TRUPATH biosensor, BRET2, Applied Microbiology
- language
- English
- id
- 9091536
- date added to LUP
- 2022-06-23 15:38:55
- date last changed
- 2022-06-23 15:38:55
@misc{9091536,
abstract = {{G protein-coupled receptors are the biggest family of membrane bound receptor in the human genome, they are also target for many drugs due to their accessible location in the cell membrane. We have characterized the G protein recruitment of the succinate receptor 1 (SUCNR1/GPR91). GPR91 was deorphanized in 2004 and already then it was suggested that GPR91 could couple to the Gi-family and the Gq-family of G proteins. Since then, the fact that it could do this have been debated. We have used and optimized the TRUPATH biosensor (Olsen et al., 2020) to show dose-response recruitment curves for both hGPR91 and mGPR91 for the Gi- and Gq-family of G proteins. We show that hGPR91 recruits all tested α-subunits of the Gi- and Gq-family whilst mGPR91 recruits all except for αQ. We also show that mGPR91 is approximately 1 order more potent than hGPR91. We conclude that the TRUPATH biosensor is a good tool for investigation of G protein recruitment, but it needs to be optimized to fit each receptor that should be investigated. Further on we suggest using the results obtained as a guide for further investigation of GPR91 structurally as well as to see if there is any bias signalling occurring.}},
author = {{Liljewall, Sofie}},
language = {{eng}},
note = {{Student Paper}},
title = {{The differential signalling of the succinate receptor SUCNR1/GPR91, through Gi versus Gq}},
year = {{2022}},
}