Prashant Donthamsetti, assistant professor of pharmacology at the School of Medicine Basic Sciences,delivered the second School of Medicine Basic Sciences Kairos Lecture to a full room on March 26.
Tina Iverson, associate dean for faculty, introduced Donthamsetti, whose laboratory develops innovative tools to probe the molecular mechanisms of G protein–coupled receptor signaling in health and disease.
Iverson cited Donthamsetti’s innovative approach to research. “His research begins with the molecular basis of GPCR signaling, then connects molecular mechanisms to neural circuits and behavior,” she said. “His focus remains around dopamine signaling, which further connects to investigators working in addiction. In that sense, his arrival in the pharmacology department reflects the theme of the Kairos seminar series: A connection between molecules and organisms involved the right person, and the right time, for the direction the department was heading.”
Donthamsetti discussed how GPCRs regulate a wide range of physiological functions and presented his recent work on signal bias, a process where GPCR signaling can be directed toward distinct functional outcomes. The concept is of both fundamental and translational importance and an area of increasing interest in drug discovery.
Biased GPCR agonists, GPCR “activators” that preferentially activate either G proteins or arrestins, offer substantial clinical potential yet have been difficult to develop. A central player in biased signaling is GPCR kinase 2, which phosphorylates GPCRs and promotes arrestin recruitment.
In the traditional view, GRK2 is recruited only after G protein activation, raising questions about whether strongly biased agonists are achievable, but Donthamsetti described data showing that many GPCRs can recruit GRK2 without prior G protein activation, resulting in distinct, biased signaling profiles. These results update the prevailing model of GRK2 action and underscore the importance of considering multiple GRK2 recruitment pathways when designing biased GPCR agonists.
At the end of the lecture, Donthamsetti responded to questions from the audience and interacted with them at a reception following the lecture.
Donthamsetti received his Ph.D. from Columbia University and completed his postdoctoral training at the University of California, Berkeley. In 2022, he joined Vanderbilt University as an assistant professor in the Department of Pharmacology. He is a member of the Vanderbilt Brain Institute, the Vanderbilt Center for Addiction Research, and the Vanderbilt Institute of Chemical Biology.
Kairos Lectures take place throughout the year on the fourth Thursday of the month in 1220 Medical Research Building III.