Structure and Molecular Characteristics

• Protease Activated Receptor 3 (PAR3) is part of the G protein-coupled receptor (GPCR) family, coded by the F2RL2 gene.
• It shares similarities with other PAR proteins in its seven transmembrane domain structure.
• The receptor includes an N-domain with a cleavage site sensitive to certain proteases, creating a new N-terminal end that functions as a ligand.
• PAR3 distinguishes itself through its unique methods of activation and regulatory roles.

Activation Mechanisms and Signalling Pathways

• PAR3 demonstrates distinctive activation patterns compared to PAR1 and PAR2.
• Thrombin is the primary physiological activator, cleaving the receptor to expose the tethered ligand sequence.
• PAR3 functions primarily as a co-receptor for PAR4, enhancing PAR4's responsiveness to thrombin.
• Initiates signaling pathways such as calcium movement and MAP kinase routes.

Physiological Functions and Tissue Distribution

• PAR3 expression exhibits a tissue-specific pattern:
• Platelets: Modulates thrombotic responses
• Vascular endothelial cells: Contributes to vascular integrity
• Neural tissues: Participates in development and neuroprotection
• Epithelial cells: Regulates barrier function and tissue organization
• Plays a vital role in maintaining tissue stability and responding to injury.
• Involvement in protecting against insults and aiding neuronal growth.
• Critical roles in vascular biology and inflammation control.

Role in Disease and Therapeutic Implications

• PAR3 dysregulation linked to:
• Cancer: Acting variably as a tumor suppressor or promoter.
• Cardiovascular Disease: Affects platelet function and clotting processes through interaction with PAR4.
• Potential target for treatments against blood clotting.
• Involvement in neurological conditions:
• Neuroprotection following stroke
• Neurodegenerative diseases
• Neural development and plasticity
• Blood-brain barrier integrity

Current Research and Future Directions

• Recent progress offers opportunities for treating conditions:
• Developing selective modulators of PAR3 function
• Understanding tissue-specific roles and regulation
• Elucidating contribution to disease processes
• Exploring potential therapeutic applications
• Targeting PAR3's co-receptor function with PAR4 for antiplatelet therapy.