Discovering new drugs that bind to G Protein-Coupled Receptors (GPCRs), which are central to almost every physiological process in our body such as vision, taste, immune response and cardiovascular regulation, has become easier, thanks to research by a team led by Dr. Arun K. Shukla from the Department of Biological Sciences and Bioengineering, Indian Institute of Technology (IIT) Kanpur.
Nearly 50 per cent of prescription drugs currently available in the market for the treatment of blood pressure, heart failure, diabetes, obesity, cancer and many other human diseases target GPCR receptors. All these drugs bind to their respective receptors and either activate or stop their signalling. The work by Dr. Shukla’s team has shown that the regulation of these receptors by these drugs can be simpler than generally thought — it can be mediated by engaging only the end of the receptor, which is called the tail of the receptor. The results were published in the journal Nature Communications.
Receptors found on the cell surface receive signals and transmit them to inside the cells. A part of the receptor is embedded in the cell membrane and the other part protrudes outside the membrane and inside of the cell. The part of the receptor that protrudes outside the membrane changes its shape whenever a stimulus in the body binds to itm. In response to this change in the outside part of the receptor, a corresponding change happens in the shape of the receptor that is positioned inside the cell. This change in the shape of the receptor positioned inside the cell allows it bind to other proteins called effectors. These effectors cause specific effects in the cell, referred to as cell signalling, which leads to physiological changes in our body.
For example, a hormone in the blood called angiotensin binds to its receptor and activates the effector protein inside the cell causing an increase in blood pressure.
In people with normal blood pressure, specific type of proteins called arrestins, which are effector proteins of GPCRs, bind to the receptor and pull it inside the cell (a process called receptor endocytosis). This prevents the angiotensin from binding to the receptor, thereby help in controlling the blood pressure.
In the case of people with high blood pressure, the prescribed drug binds to the receptor. So even if angiotensin is present on the surface of the cell, it cannot bind to the receptor and start the signalling process that increases blood pressure.
“We were interested in understanding how different receptors interact with effectors and how the receptors recognise the stimuli,” says Dr. Shukla. “We looked at the interaction of a receptor, which is a target for heart failure drugs, with its specific effectors, namely arrestins. When arrestins bind to the receptor, they arrest or disrupt the receptor signalling.”
“The text book understanding is that arrestins have to simultaneously bind at two sites — the tail of the receptor and the core of the receptor — for the drug to become effective in pulling the receptor inside the cell [to prevent the stimuli from binding to the receptor and start signalling],” says Dr. Shukla. “Through specific engineering of the receptor we basically disrupted one of the two binding sites, namely the core of receptor. We found that even without the second site, the arrestin was able to pull the receptor inside the cell by binding just to the tail of the receptor [which is the other binding site].”
There is a key region in the core which the team genetically deleted thereby making the core of the receptor ineffective.
“Whenever researchers are designing a drug to stop GPCR signalling, they look for a drug that simultaneously triggers the binding of arrestins to both the sites in the receptor. Our work changes the way people will look at drug discovery for GPCR signalling,” he says. “The drug has to trigger binding of arrestin to just at the tail of the receptor to arrest the signalling. Researchers can now design simple drugs to accomplish this.”