Research Interests

We have shown that two different functional responses induced by PAR-1 can be preferentially activated depending on the mode of receptor activation: 1) enzymatic cleavage by thrombin or 2) direct activation by addition of exogenous agonist peptide. These observations lead us to hypothesize that different receptor conformations are achieved by the different means of activation (agonist peptide or thrombin) thereby affecting G protein coupling abilities.

In addition to and complementary with this concept of ligand-induced functional selectivity, there is growing evidence of functional roles of GPCR dimerization in modulating downstream signaling networks. Both homo- and hetero-receptor dimers have been identified and the resulting effects on signaling have been characterized in several GPCR systems. In PARs, receptor/receptor interactions have been observed such as transactivation of PAR-2 by the cleaved tethered ligand of PAR-1 or PAR-3 behaving as a cofactor to present thrombin for efficient cleavage of PAR-4. However, direct evidence of PAR dimerization has not yet been achieved. Though it is evident that certain functional responses require the co-activation and/or transactivation of multiple PARs, the effects of receptor/receptor interactions on downstream G protein coupling and subsequent signaling have not been explored. Our initial observations of differences in signaling between agonist peptide and thrombin activation, the ability of PARs to interact with each other and the heterogeneous expression patterns of the PARs within the vasculature lead us to pose a second hypothesis that differences between agonist peptide and thrombin signaling arise from differences in the ability of the receptors to homo- or hetero-dimerize. The complex signaling initiated by PARs in endothelial cells is likely a product of these two related hypotheses. It is the objective of my work to address the validity of each and determine the physiological importance.