The Role of the Third Intracellular Ring of GPCR in GPCR Signal Conduction Mechanism

In a new study, American researchers have discovered the role of the third intracellular loop of GPCR in the GPCR signal transduction mechanism, indicating the possibility of adopting more targeted drug discovery methods and developing new drugs.

 

More than one-third of the drugs approved by the United States Food and Drug Administration (FDA) function by targeting G protein-coupled receptors (GPCRs). The human body has over 800 types of GPCRs, which provide cells with information about the external environment to calibrate the body’s response. Drugs that block or activate GPCR are used to treat a wide range of diseases, including hypertension, pain, and inflammation. The external binding of most drugs to GPCR can lead to adverse side effects, as different types of GPCR tend to be similar to each other.

 

 

In a new study, Professor Sivaraj Sivaramakrishnan of the School of Biological Sciences at the University of Minnesota in the United States, together with graduate student Fred Sadler and coauthors Michael Ritt and Yatarth Sharma, discovered the role of the third intracellular loop of GPCR in the GPCR signal transduction mechanism, indicating the possibility of adopting more targeted drug discovery methods and developing new drugs. The relevant research results were published in the journal Nature, with the title of “Autoregulation of GPCR signaling through the third internal loop”.

 

Sivaramakrishnan said, “Typical GPCR targeted drugs act as an on or off switch for cell signal transduction results. Drugs that effectively utilize the third intracellular loop of GPCR can serve as a signal transduction regulatory switch to more accurately control drug reactions.”

 

These authors have developed new biochemical and biophysical tools that combine computational measurements by collaborators Ning Ma and Nagarajan Vaidehi of the City of Hope Cancer Center. They tracked how the shape or conformation of the third intracellular ring of GPCR changed during GPCR signal transduction. In a breakthrough in this field, their data show that the third intracellular loop of GPCR acts like a gate, ensuring that GPCR activates the correct type of G protein signaling at the correct intensity.

 

Sadler said, “A key advantage of the third intracellular loop of GPCR is that it is very unique, even in closely related GPCRs, making it an excellent drug target. Developing drugs through this newly discovered mechanism will greatly enhance the targeting of treatment methods.”

 

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Reference

Fredrik Sadler et al. Autoregulation of GPCR signalling through the third intracellular loop. Nature, 2023, doi:10.1038/s41586-023-05789-z.