The Endoterpenoid System: A Membrane-Based Logic Framework for Integrating Cannabinoid, Olfactory, and...

Area of Science:

• Biochemistry and Molecular Biology
• Cellular Signaling
• Microbiome Research

Background:

• Classical endocannabinoid signaling (ECS) involves G protein-coupled receptors (GPCRs) and endogenous cannabinoids.
• Olfactory receptors (ORs) and microbial metabolites are increasingly recognized for roles beyond their primary functions.
• Lipid rafts and receptor heteromerization are known to modulate cellular signaling pathways.

Purpose of the Study:

• To propose a novel membrane-based framework, the Endoterpenoid System (ETS).
• To integrate ECS with ectopically expressed olfactory GPCRs, ion channels, and microbially derived terpenoids.
• To introduce the concept of the endoterpenoidome (eTBome) as a pool of bioactive lipids and terpenoids.

Main Methods:

• Detailed molecular mechanisms including lipid-mediated allostery, scaffold protein recruitment, and lateral diffusion.
• Utilized germ-free and antibiotic-treated animal models to assess microbial influence.
• Proposed experimental validation strategies: structural studies, lipidomic mapping, super-resolution imaging, and gnotobiotic manipulations.

Main Results:

• The ETS framework explains co-localization and co-expression of signaling components within lipid rafts.
• Receptor heteromerization and β-arrestin scaffolding facilitate dynamic crosstalk and emergent signaling responses.
• Gut microbiota are identified as key architects of the eTBome through terpene synthase activity, influencing ETS ligand pools and receptor distributions.

Conclusions:

• The ETS/eTBome concept provides a cohesive hypothesis for lipid-driven GPCR crosstalk.
• This framework integrates ECS, olfactory receptors, and microbial metabolites.
• Identified potential non-standard therapeutic targets for cancer, neuroinflammation, and metabolic disorders.