Direct interrogation of context-dependent GPCR activity with a universal biosensor platform.

Area of Science:

• Molecular and Cellular Biology
• Pharmacology
• Biotechnology

Background:

• G protein-coupled receptors (GPCRs) are a major class of drug targets, but understanding their function is limited by the lack of suitable measurement tools.
• Existing methods struggle to accurately assess GPCR behavior in complex, physiologically relevant cellular environments, hindering drug discovery and development.

Approach:

• Developed a novel platform of compact ONE vector G-protein Optical (ONE-GO) biosensors for scalable and high-fidelity measurement of GPCR activity.
• Designed biosensors for broad applicability, enabling the study of virtually any GPCR, including those expressed endogenously in primary cells like neurons and cardiovascular cells.
• The ONE-GO system facilitates direct interrogation of GPCRs in their native cellular contexts, overcoming limitations of traditional assays.

Key Points:

• Characterized numerous GPCRs across diverse cell types, revealing novel insights into G-protein coupling selectivity and signaling bias.
• Investigated pharmacogenomic profiles of antipsychotic drugs, identifying differential responses based on naturally occurring GPCR variants.
• Discovered cell-type-specific and disease-state-dependent variations in G-protein subtype signaling by endogenous GPCRs.

Conclusions:

• The open-source ONE-GO biosensor platform provides a powerful and accessible tool for studying context-dependent GPCR activity.
• This technology advances our understanding of GPCR molecular mechanisms, drug actions, and disease pathophysiology.
• Enables broader research into GPCR signaling in primary cells and disease models.