Research Alerts
How One Receptor Can Help — or Hurt — Your Blood Vessels
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Key Takeaways
- A single receptor in blood vessels can trigger either harmful inflammation or protective healing, but scientists have struggled to understand how this is possible.
- UC San Diego researchers revealed how this molecular switch works.
- Insights may help advance treatments for sepsis, heart attack, stroke and other inflammatory conditions.
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:
- Both protective and harmful PAR1 responses are orchestrated by the same intermediate enzyme, called GRK5, but the response is different depending on the location of GRK5 within cells.
- For PAR1 to trigger a protective response, GRK5 must be anchored to the cell’s plasma membrane – the barrier separating the cell from its surroundings.
- For PAR1 to trigger a harmful response, GRK5 can act from within the cytoplasm – the fluid within cells.
- Models created with the Nobel-prize winning artificial intelligence (AI) modeling tool AlphaFold 3 revealed that different cuts to the outside portion of PAR1 determines how it behaves inside the cell.
“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.
This diagram illustrates the two different responses triggered by PAR1. PAR1 can trigger inflammation when activated by thrombin (left) or protection when activated by APC (right). GRK5 and β-arrestin2 each play key roles in these processes, but in different ways depending on the activator.
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