GPCR function and regulation in health and disease
GPCRs regulate essentially every physiological process in humans, including vital brain functions underlying behavior. We want to ultimately link what we learn about the cellular function and regulation of these receptors to physiology and pathophysiology. As a step towards this goal, we are examining how the spatial, biochemical and pharmacological regulation of GPCRs shapes important neuronal functions at the cellular level.
We are currently focusing on:
1) Understanding the functional consequences of compartmentalized GPCR/cAMP signaling in primary neurons. The concept of location-based signaling is particularly interesting in neurons due to their large size and structural specialization, and we are evaluating how site-specific receptor signaling underlies neuronal activity and activity-dependent transcription and translation.
2) Investigating how the spatial and biochemical regulation of receptor signaling is impacted in human diseases using iPSC-derived neurons. Using a biosensor that recognizes the active conformation of the beta-adrenergic receptor, we detect active GPCR on endosomes in these cells (see Figure).
Figure. Active B2-AR on endosomes of human iPSC-derived neurons. A nanobody bionsensor (Nb80) detects active flag-tagged receptor (red).
For reference, see:
Semesta KM, Garces A and Tsvetanova NG. (2023). The psychosis risk factor RBM12 encodes a novel repressor of GPCR/cAMP signal transduction. The Journal of Biological Chemistry 299: 105133.