Protease-Activated Receptors Overview

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Questions and Answers

What is the role of serine proteases in relation to PAR family receptors?

They enhance receptor binding by increasing ligand concentration.

They block receptor activity through competitive inhibition.

They provide structural support to the receptors.

They induce proteolysis to activate or inactivate the receptors. (correct)

Which of the following cellular actions is NOT mentioned as a contribution of the PAR family?

Homeostasis

Inflammation

Cell survival

Cell division (correct)

Which cleaving agent specifically acts on PAR2?

Neutral endopeptidase

Thrombin

Cathepsin G

Trypsin (correct)

Which action is performed by thrombin related to PARs?

Activates PAR1 Signup and view all the answers

What two signaling pathways are primarily affected by the PAR family?

Rho and Ras activation, calcium signaling Signup and view all the answers

Which enzymes are specifically mentioned to cleave active soluble hormones?

TACE and ACE Signup and view all the answers

What type of elements comprise about 2% of the human genome?

G-protein coupled receptors Signup and view all the answers

Which residue is essential in the catalytic domain of serine proteases?

Serine Signup and view all the answers

What role does the Hirudin-like site play in thrombin binding?

It enhances binding to PAR 1 and 3. Signup and view all the answers

Which statement about PAR 3 is correct?

PAR 3 can activate PAR 4 upon cleavage. Signup and view all the answers

What are the two types of PAR internalization?

Constitutive and activated PARs internalization. Signup and view all the answers

Which internalization mechanism is known for regulating receptor activity post-activation?

Clathrin coated pits mediated internalization. Signup and view all the answers

How does the cleaved receptor interact with uncleaved receptors?

It can activate the uncleaved receptor. Signup and view all the answers

What is the function of the tethered ligand domain in relation to PAR?

It interacts with EGFR. Signup and view all the answers

PAR 4 is unique in its lack of which feature?

Hirudin-like site. Signup and view all the answers

What percentage of known GPCRs in the human genome is classified as Class I orphans?

39% Signup and view all the answers

What term is used to refer to receptors whose endogenous ligands have not yet been identified?

Orphan receptors Signup and view all the answers

What approach is mentioned in the context of drug discovery for orphan receptors?

Reverse pharmacology Signup and view all the answers

Which of the following is an example of an adopted orphan receptor in the GPCR family?

Orexin receptor Signup and view all the answers

How are orphan receptors generally designated in nomenclature?

GPR followed by a number Signup and view all the answers

What percentage of Class I receptors in the human genome are classified as known?

39% Signup and view all the answers

What is the range of GPCRs in the human genome with identified ligands?

Around 210 Signup and view all the answers

Which method is NOT mentioned as a measure for assessing receptor activity?

Protein synthesis measurement Signup and view all the answers

Study Notes

Protease-Activated Receptors (PARs)

PARs are a family of G protein-coupled receptors (GPCRs) activated by proteolytic cleavage.
Proteolytic cleavage exposes a tethered ligand domain within the receptor, which then binds and activates the receptor, initiating signaling cascades.
The cleavage is usually performed by serine proteases.
Examples of serine proteases that activate PARs include thrombin (acts on PAR1, 3, and 4) and trypsin (acts on PAR2).
PARs contribute to tissue responses to injury including repair, homeostasis, cell survival, inflammation, and pain transmission.
PARs function through the actions of various pathways including Gi (cAMP inhibitory), 12/13 (Rho and Ras activation), and q (calcium signaling).
Proteases comprise roughly 2% of the human genome, and have diverse biological functions, often including cleaving a ligand or receptor.

Orphan Receptors

Orphan receptors are GPCRs with no identified endogenous ligand.
There are approximately 210 known ligand receptors, and 160 receptors with unknown ligand or function.
Half of the human genome encodes sensory receptors, with approximately 360 receptors.
If an orphan receptor's ligand is discovered later, the receptor is termed an "adopted orphan receptor" and is usually given the GPR followed by a number (e.g., GPR1).
Classification of known and orphan GPCRs: 39% class I known, 37% class I orphans, 6% class II orphans, and 5% class II known.

Identification of Ligands/Deorphanization

Methods of identifying ligands for orphan receptors include:
- Screening known ligands (e.g., from compound libraries).
- Screening biological extracts (e.g., from biological sources).
Methods include an assay following screening to identify potential ligands.
"Reverse pharmacology" is a useful approach.
Assays include calcium measurement, cAMP measurement, internalization of tagged receptors, arachidonic acid release (PLA2), and electrophysiology.

Examples of Adopted Receptors

Examples of adopted orphan receptors (part of the GPCR family) include the histamine H4 receptor, orexin receptor, and prolactin-releasing peptide receptor.
Examples of adopted orphan receptors (part of the nuclear receptor group) include farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptor (PPAR).

Proteases for PARs

Thrombin acts on PARs 1, 3, and 4; Trypsin acts on PAR 2.
Many proteases are produced during tissue damage.
Many proteases rely on serine residues in their catalytic domains to induce proteolysis.
Cleavage sites often include Lysine (K) and Arginine (R).
Examples of Proteases:
- TACE and ACE

Example Proteases

TACE and ACE cleave the precursors of active soluble hormones.
Neutral endopeptidase inactivates neuropeptide substance P.
Cleavage of special GPCRs (PARs) on cell membranes can cause receptor activation.

PAR Activation

Thrombin binds to PAR 1/3 due to the presence of a hirudin-like site.
It cleaves the peptide sequence of the receptor's N-terminal and allows the binding of tethered ligands to the receptor.
Binding to one receptor can facilitate cleavage of another receptor on the same cell (e.g. PAR3 and PAR4).

PAR Internalization

There are two types of PAR internalization: constitutive and agonist-induced internalization.
Following activation, PARs are regulated by ubiquitin-mediated internalization and clathrin-coated pits mediated internalization.

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Description

This quiz covers the key concepts of protease-activated receptors (PARs), including their activation mechanisms, the types of proteases involved, and their biological significance. Additionally, the quiz touches on orphan receptors and their characteristics as G protein-coupled receptors. Test your knowledge on these essential components of cellular signaling!