GPCR endocytosis rewires neuronal gene expression and cellular architecture

Area of Science:

• Neuroscience
• Molecular Biology
• Cellular Signaling

Background:

• G protein-coupled receptors (GPCRs) are crucial for neuronal function, influencing excitability, synaptic transmission, and behavior.
• The precise molecular mechanisms linking GPCR activation to long-term neuronal adaptations, including changes in cellular function and architecture, are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which GPCRs, specifically the beta-adrenergic receptor (β2AR), induce structural remodeling in neurons.
• To investigate the compartmentalized signaling pathways and gene regulation layers involved in β2AR-mediated neuronal adaptations.

Main Methods:

• Utilized the beta-adrenergic receptor (β2AR) as a model GPCR in the central nervous system.
• Investigated signaling pathways involving protein kinase A (PKA), cAMP response element-binding protein (CREB), and the mechanistic target of rapamycin (mTOR).
• Analyzed gene transcription and protein translation related to neuronal morphogenesis and protein synthesis machinery.

Main Results:

• Demonstrated that stimulated β2ARs remain active on endosomes, driving intracellular signaling.
• Showed that β2AR signaling promotes dendritic growth and synapse formation.
• Identified two key regulatory axes: PKA/CREB-dependent gene transcription and PKA/mTOR-dependent translation.

Conclusions:

• GPCR signaling, exemplified by β2AR, drives neuronal structural reorganization through compartmentalized pathways.
• Novel spatial and biochemical principles govern how GPCRs orchestrate gene regulation for enduring functional adaptations in neurons.
• This research provides a framework for understanding GPCR-mediated plasticity in the brain.