Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review

Figure 1

Activation of protease-activated receptor 2. (a) PAR2 is a seven-transmembrane domain cell surface receptor that can be activated by serine proteases which recognize a substrate sequence on the N-terminus (-NH₂) located in the extracellular space. To highlight the unique mechanism of action a simplified cartoon shows the arrangement of the nonactivated PAR2 protein sequence (ribbon) in a cell plasma membrane. Asterisk indicates the site of proteolytic cleavage of mouse and rat PAR2 associated with serine proteases, including trypsin, human mast cell β-tryptase, matriptase, and several human kallikreins. (b) Following proteolytic cleavage, the newly revealed N-terminus (shown as  LRGILS) acts as a tethered ligand that interacts (solid arrow) with the extracellular loop-2 (ECL-2) domain and induces the activated state of the receptor. Alternatively, receptor activating peptides (2fLIGRLO, SLIGRL, and SLIGKV), and nonpeptide agonists (GB110) can activate PAR2 without the participation of proteases (dashed arrow). Also, shown are the proposed sites of action of different classes of PAR2 antagonists, that is, GB83, GB88 (dashed arrow) and PAR2 pepducin P2pal-14GQ (oval arrow). Peptide sequences are identified by their amino acid sequences using the standard capitalized one-letter abbreviations. All PAR2 activating peptides were synthesized as amides. Sequence starting with 2f indicates N-terminal modification with a 2-furoyl functional group. COOH: carboxy terminus; ECL: extracellular loops domains 1 to 3; ICL: intracellular loop domains 1 to 3; TM: transmembrane loop domains 1 to 7.

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