There are three known thrombin receptors (ThrR), termed PAR1, PAR3 and

PAR4 Protease-activated receptor 4 (PAR-4), also known as coagulation factor II (thrombin) receptor-like 3, is a protein that in humans is encoded by the ''F2RL3'' gene. Function Coagulation factor II (thrombin) receptor-like 3 (F2RL3) is a member ...

(PAR for

protease-activated receptor Protease-activated receptors (PAR) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, myocytes an ...

G-protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

that are responsible for the

coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

effects and responses of thrombin on cells are known as protease-activated receptors, or PARs. These receptors are members of the

7-transmembrane G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

g protein-coupled G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

family of

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

s, however, their method of activation is unique. Unlike most G-protein-coupled receptors, PARs are irreversibly activated by proteolytic mechanism and therefore, are strictly regulated.

Thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...

is an allosteric

serine protease Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. ...

that is an essential effector of coagulation that is produced at sites of vascular injury and plays a critical role in cellular response to blood-related diseases. It binds to and cleaves the extracellular

N-terminal domain The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

of the receptor. A tethered

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

corresponding to the new

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

, SFLLRN, is then unmasked, binding to the second extracellular loop of the receptor and activating it.

Tissue distribution

PAR1, PAR3, and

are activated by thrombin. There are species-specific differences in thrombin receptor expression in platelets and other cell types, in which differences in thrombin concentrations may considerably affect platelet activation of distinct PARs. As seen in human platelets, PAR1 and PAR4 are the functional thrombin receptors, whereas PAR3 and PAR4 are functional thrombin receptors in mouse platelets Thrombin receptors are also differentially expressed in cell types, e.g. PAR1 is expressed in

fibroblast A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...

smooth muscle cells Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...

sensory neuron Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded potentials. This process is called sensory transduction. The cell ...

s and

glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...

, whereas the other two are less clearly defined. There are various roles depending on location of activation.

Fibroblast A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...

s and

induces growth factor and matrix production, migration and proliferation.

Sensory neuron Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded potentials. This process is called sensory transduction. The cell ...

s induces proliferation and release of neuroactive agents.

Regulation of signaling

Desensitization and

Internalization Internalization ( or internalisation) is the process of making something internal, with more specific meanings in various fields. It is the opposite of externalization. Psychology and sociology In psychology, internalization is the outcome of ...

Initial desensitization due to rapid phosphorylation of activated receptors by

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

s, which increases affinity for

arrestin Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of ...

. Arrestin prevents protein-receptor interaction and the receptor becomes dephosphorylated and inhibited from signaling. This is a sufficient and rapid form of termination of PAR signaling. Irreversibly activated PAR1 is internalized and terminated from further signaling by

clathrin-mediated endocytosis Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This ...

and

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...

degradation, preventing replenishment at the cell surface.

References

G protein-coupled receptors {{Biochem-stub