G protein-coupled receptors (GPCRs) are involved in all important aspects of human physiology and have become prime targets for therapeutic intervention. Dr. Nina Tsvetanova’s lab aims to understand how GPCRs work at the cellular level and ultimately leverage this information to enhance the ability to develop more specific and efficient therapies for treating human disease. Their study “Endosome positioning coordinates spatially selective GPCR signaling” published in Nature Chemical Biology is led by recent PCB alum, Dr. Blair Willette, and discovers a new principle underlying receptor signal specificity.
Findings from the Tsvetanova lab have contributed to a recent paradigm shift in the field by revealing that GPCR signaling originates not only at the cell surface, but also from intracellular organelles. Ultimately, this second wave of signaling gives rise to distinct downstream responses, shapes the selectivity of drugs and drug-dependent physiology. Therefore, this principle could be exploited to improve therapeutic strategies targeting these pathways. But to do so, we need to understand how the same GPCR generates different outcomes depending purely on its subcellular site of activation. The study by the Tsvetanova lab demonstrates that an intrinsic biophysical property of early endosomes, namely their precise three-dimensional perinuclear positioning within the cell, plays a principal role in enabling compartmentalized GPCR activity. More intriguing, this regulation is completely uncoupled from the biochemical makeup of endosomes. These findings raise important questions about how endosome positioning is regulated across tissues, in normal cells and in disease, by nutrients and other extracellular signals, during cell division and stress, as these would be predicted to alter the repertoire of responses that can occur downstream of intracellular GPCRs.