Researchers at the University of California San Diego have uncovered how a single protein triggers two opposite responses in blood vessels — one inflammatory and one protective. This protein, a cell-surface receptor called protease-activated receptor-1 (PAR1), plays a critical role in maintaining the structural integrity of our blood vessels. Understanding how PAR1 switches between healing and harmful signaling pathways could pave the way for new treatments for conditions marked by vascular inflammation and leakage, including sepsis, heart attack and stroke.
PAR1 sits on the surface of the thin layer of cells lining blood vessels and is activated by being chemically cut by one of two enzymes. One of these pathways leads to a harmful PAR1 response that causes inflammation and leakage, while the other triggers a protective response that counteracts inflammation. Until now, scientists haven’t understood how it’s possible for a single molecule to be activated in two such opposing ways.
The new study found:
“Our findings provide a detailed molecular explanation for how PAR1 can send such dramatically different messages depending on the activating enzyme,” said corresponding author JoAnn Trejo, PhD, professor of pharmacology at UC San Diego School of Medicine.
“This opens the door to therapies that could harness the protective response of PAR1 without potentially triggering the opposite response,” added co-corresponding author Irina Kufareva, PhD, professor at the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences.
In addition to Trejo and Kufareva, the study, published in Cell Reports , was led by Monica L. Gonzalez Ramirez, PhD, and Lennis B. Orduña-Castillo, PhD. The study was supported by the NIH National Heart, Lung and Blood Institute and the American Heart Association. The authors report no competing interests.
Cell Reports