2026 GNAO1 Conference (Day 1, Session 18) - Henrik G. Dohlman, PhD

GNAO1 Disorder and Regulators of G-protein Signaling Henrik G. Dohlman, PhD University of North Carolina at Chapel Hill, USA Heterotrimeric G proteins are transducers for a variety of neurotransmitter receptors. In a screen of disease-linked mutations in Gnao1, we identified a subset that had no obvious biochemical defects, warranting further investigation. By structural modeling, protein-protein binding experiments in vitro and in cells, as well as measures of downstream ion channel electrophysiology, we identified a subset that impair interactions with Regulator of G protein Signaling (RGS) proteins. RGS proteins accelerate G protein GTPase activity and are therefore critical for proper neurotransmitter signaling. Synthesis of clinical data revealed that patients harboring these variants have comparatively mild symptoms. Our analysis demonstrates the importance of RGS regulation in G protein function, cell signaling, and human neurobiology. Henrik Dohlman is a Professor and Chair of Pharmacology at the University of North Carolina, where he conducts discovery driven research on G proteins. Dohlman earned his PhD with Nobel laureate Robert Lefkowitz, and contributed to the first sequencing of a G protein-coupled neurotransmitter receptor. He has advanced understanding of G protein signaling and desensitization, with discoveries that have opened new avenues for drug development, including the identification of RGS proteins. While neurotransmitter receptors activate G proteins, RGS proteins act as molecular brakes, inactivating G proteins by accelerating their catalytic activity. This established a new paradigm for how cells desensitize to persistent stimuli, with direct implications for understanding drug tolerance and addiction. His current research investigates how genetic variants linked to epileptic encephalopathies alter the cell's response to neurotransmitters and drugs.