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2016 ; 128
(2
): 169-77
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Protease-activated receptors in hemostasis
#MMPMID27127302
Nieman MT
Blood
2016[Jul]; 128
(2
): 169-77
PMID27127302
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Protease signaling in cells elicits multiple physiologically important responses
via protease-activated receptors (PARs). There are 4 members of this family of
G-protein-coupled receptors (PAR1-4). PARs are activated by proteolysis of the N
terminus to reveal a tethered ligand. The rate-limiting step of PAR signaling is
determined by the efficiency of proteolysis of the N terminus, which is regulated
by allosteric binding sites, cofactors, membrane localization, and receptor
dimerization. This ultimately controls the initiation of PAR signaling. In
addition, these factors also control the cellular response by directing signaling
toward G-protein or ?-arrestin pathways. PAR1 signaling on endothelial cells is
controlled by the activating protease and heterodimerization with PAR2 or PAR3.
As a consequence, the genetic and epigenetic control of PARs and their cofactors
in physiologic and pathophysiologic conditions have the potential to influence
cellular behavior. Recent studies have uncovered polymorphisms that result in
PAR4 sequence variants with altered reactivity that interact to influence
platelet response. This further demonstrates how interactions within the plasma
membrane can control the physiological output. Understanding the structural
rearrangement following PAR activation and how PARs are allosterically controlled
within the plasma membrane will determine how best to target this family of
receptors therapeutically. The purpose of this article is to review how signaling
from PARs is influenced by alternative cleavage sites and the physical
interactions within the membrane. Going forward, it will be important to relate
the altered signaling to the molecular arrangement of PARs in the cell membrane
and to determine how these may be influenced genetically.
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