Marvin T. Nieman, PhD
Assistant Professor, Pharmacologynieman@case.edu 216.368.0250 (o) 216.368.1300 (f)
Member, Molecular Oncology Program
The underlying theme of my research program is that protease-activated receptor subtypes interact with one another to mediate the full range of thrombin signaling for activation of platelets and endothelial cells. Thrombin is a potent platelet agonist that signals through PAR1 and PAR4 to mediate adhesion and aggregation. PAR4 is associated with a prolonged stimulus as measured by intracellular Ca2+-mobilization and may be required for stable clot formation. The rate of PAR4 activation by thrombin is enhanced ~10 fold due to a thrombin-dependent association with PAR1. Heterodimerization may be a common theme for regulating signaling because three major platelet GPCRs (PAR1, PAR4, P2Y12) have agonist depending interactions. PAR4 is at the center of this group of receptors since it interacts with both PAR1 and P2Y12. Moreover, PAR1 and P2Y12 are the targets of vorapaxar and clopidogrel, respectively, which makes PAR4 the primary receptor for patients on these therapies. The increased reliance on PAR4 in this setting may have particular importance given the recent observation that there are race differences in PAR4 reactivity.