What are G-protein coupled receptors (GPCRs) and what role do they play in the body?
GPCRs are one of the largest families of cellular signalling proteins consisting of more than a thousand different types. They reside on the surface membranes of cells where they are poised to recognize molecules in the exterior environment and then transmit this information through the membrane allowing cells to respond accordingly.
GPCRs are involved in virtually all of the physiological processes in the body; some examples are our senses of sight and smell, neurotransmission, the “fight or flight response”, the regulation of the immune system and inflammation, a process that occurs during infections and in many other diseases.
Why are GPCRs the target of many medications?
GPCRs control processes that occur in many pathologic situations, so drugs that target the GPCRs may modify the severity of the particular condition. GPCRs’ exposure on the cell surface allows them to be easily targeted by small synthetic molecules (drugs).
Can you give an introduction to your recent research that was published in JCI?
Because they are so important in physiology and disease, GPCRs have been intensely studied, yielding a wealth of information about their activities, structures and mechanisms.
An area that is less understood is where and when they are activated in the body because of the difficulty in identifying one particular activated GPCR in the midst of many in a whole organism like a mouse.
To get this information we engineered a mouse that gives a map of where one GPCR, called S1P1, is activated.
Why did you choose to focus on the sphingosine-1-phosphate receptor 1 (S1P1) GPCR?
We focused on the S1P1 receptor because it has important functions in the cardiovascular system, and during immune response and inflammation. S1P1 is also the target of a drug that treats multiple sclerosis.
S1P1 is one of the most abundant of all the GPCRs, so it makes a great model for their understanding.
What were the main challenges in understanding the mechanisms of S1P1 in vivo?
S1P1 is expressed on many cell types so it is difficult to know when and where it was activated normally and during diseases.
Also, since GPCRs transmit their signals to cells in similar ways, it is hard to know if a cell was getting a signal from S1P1 or from one of the many other GPCRs that might be activated.
How did you identify the sites of S1P1 activation?
With our mouse model, cells that have an activated S1P1 receptor turn green. We first mapped the cells that had an activated receptor in normal mice. We then produced inflammation in the mice by mimicking a bacterial infection and mapped the cells with a newly activated receptor.
In this way we were able to identify the cells that become activated through S1P1 during inflammation.
What impact do you think your research will have on the understanding of S1P1?
I think it will enable us to know if S1P1 is involved in a particular physiological process or disease. It will also help us understand the important role S1P1 has in inflammation.
Do you think the new mouse model will help in the development of new medicines to combat diseases where inflammation is involved?
Yes, the new mouse model will also allow us to test drugs for S1P1 much more easily.
Could your methodology be applied to other GPCRs?
Yes. It should be possible to use the same basic design to produce similar mice to study other GPCRs.
Where can readers find more information?
About Dr. Richard Proia
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Bates College, BA
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University of Texas Southwestern Medical Center, PhD
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Chief, Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH
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