Dr. Mithu Baidya’s interview with Bio Patrika hosting “Vigyan Patrika“, a series of author interviews. Dr. Baidya is currently a postdoc in the lab of Prof. Arun Shukla in the department of Biological Sciences and Bioengineering at the Indian Institute of Technology Kanpur, India. He published a paper titled “Key phosphorylation sites in GPCRs orchestrate the contribution of β‐Arrestin 1 in ERK1/2 activation” as the first author in EMBO reports (2020).
How would you explain your paper’s key results to the non-scientific community?
Our research published in EMBO reports explains the molecular basis of side effects caused by drugs, targeting a special type of receptor called G protein coupled receptors (GPCRs). Almost 40% of current drugs target these GPCRs for treating several clinical conditions. Therefore, the study has enormous implications in designing the next generation of safer drugs having very minimal side effects.
GPCRs are membrane proteins that act as a mailbox that receives several messages in the form of hormones or drugs and relays the information from the external environment to the cell machinery for a response in a coded massaging system inside the cell, which we call as signaling (Figure 1). GPCRs have two main partners who serve as a pivotal point for disbursing the signal viz. G proteins and beta-arrestins. GPCRs, upon receiving signal/massage undergo a modification called phosphorylation i.e., the addition of phosphate group on Serine and Threonine amino acids present in their terminal tail. This phosphorylation serves to act as a code that beta-arrestins recognizes and binds the receptor and initiates signaling in the cells.
Figure 1: GPCR behaves like a mailbox that receives messages from outside the cell and relays them to cell machinery by signaling.
Typically, GPCR signaling involves ERK1/2 MAP kinase proteins, which play an essential role in cellular growth and proliferation. For most of the GPCRs, lowering the level of beta-arrestins typically reduces ERK1/2 activation, but for some GPCRs, it leads to an enhancement. This phenomenon of opposing contribution of beta-arrestin in different receptors was inexplicable with our current understanding. It was quite a puzzling mystery in the field for more than two decades.
In this study, we took two such GPCRs vasopressin 2 receptor and bradykinin 2 receptor which is known to have an opposing effect in ERK activation upon beta-arrestin depletion. To unclutter this puzzle, we designed a smart and simple experimental approach whereby we changed the arrangement of the code i.e. position of Serine and Threonine amino acids in the tail of the human bradykinin receptor, a GPCR that is involved in cardiovascular regulation and pain sensation. By even a slight rearrangement of the code in bradykinin receptor C tail, we observed a dramatic alteration in the inhibitory contribution of beta-arrestin 1 in ERK1/2 activation to a more supportive role. We further discovered that such a change in the receptor C tail code does not affect the overall physical binding of beta-arrestin 1 to the bradykinin receptor but it rather changes its conformation (i.e. overall shape of beta-arrestin 1), which in turn determines beta-arrestin’s ability to support ERK1/2 activation in the cells (Figure 2).
Figure 2: Conformation of beta-arrestin (βarr) in vasopressin 2 receptor stimulates ERK signaling but a different beta-arrestin conformation in bradykinin 2 receptor is inhibitory to ERK activation but when Bradykinin 2 receptor mutant with a changed code, made similar to vasopressin 2 receptor now induce a conformation in beta-arrestin which again becomes supportive of ERK activation.
What are the possible consequences of these findings for your research area?
More than one third of all marketed medicines target the GPCRs to treat a wide variety of ailments. Understanding the details of GPCR signaling and regulation has critical implications for making smarter medicines with a minimized side-effect. Therefore, our findings now provide a previously missing piece of information about how conformation (overall shape) of beta-arrestins can control GPCR signaling, and therefore, have the potential to contribute towards improving GPCR targeting medicines in the future.
“[…] a paradigm-changing contribution to the field to understand beta-arrestin plasticity and related functions better.”
What was the exciting moment (eureka moment) during your research?
Conformation drives specific functions of beta-arrestin 1, which is a big finding of the study. Our preliminary study showed that beta-arrestin 1 exists in distinct conformation in different GPCRs first established in vasopressin and bradykinin receptor systems. It turned out to be a ‘Rosetta stone’ to decrypt this opposing beta-arrestin function in the other receptors. This is a paradigm-changing contribution to the field to understand beta-arrestin plasticity and related functions better. I feel this was the inflection point in the whole study, which made us so upbeat to follow this up to its logical conclusion.
What do you hope to do next?
Our next big aim is to identify the conformations of beta-arrestin, which favors biased signaling focused more towards the GPCR-beta-arrestin axis in different GPCRs, which will help us generate next-generation drugs with much lesser side effects in many more GPCRs. Our focus will be more towards those GPCR whose alternation is known to cause critical diseases in humans.
Where do you seek scientific inspiration?
Getting a new piece of data that crystallizes my hypothesis (in many cases opposing it) is a treat of delight, and this unsettles me (in the right sense, of course) and gives me the drive to chase it for months to come. Finally, when peers appreciate these discoveries makes me feel I am moving in the right direction.
How do you intend to help Indian science improve?
I am not sure how I can improve Indian science, but I want to enhance or intend to improve the pharmaco-profile in the context of side effects caused by current GPCR drugs. By understanding the finer details of the beta-arrestin signaling paradigm, we can design much safer drugs with lesser side effects, which will bring relief to patients undergoing treatments with GPCR drugs. GPCR research has not picked up in India the way it should have been, especially keeping in mind India’s massive production output in global pharmaceutical manufacturing. This is quite a paradox really, and can be explained by the fact India does not discover or identify new GPCR drugs but rather produce the generic ones for foreign labels. This has to improve and can only be done by a higher focus in GPCR research in academia and the pharma industry. Let’s hope we only improve in the coming years.
Baidya M, Kumari P, Dwivedi-Agnihotri H, Pandey S, Chaturvedi M, Stepniewski TM, Kawakami K, Cao Y, Laporte SA, Selent J, Inoue A, and Shukla AK. Key phosphorylation sites in GPCRs orchestrate the contribution of β-Arrestin 1 in ERK1/2 activation. EMBO Rep. 2020; 21(9): e49886.