56 Questions
What is the structure of a GPCR?
7 transmembrane protein with N term in extracellular part and C term in intracellular
How many receptors within the GPCR SuperFamily have unknown function?
More than 600
What happens to GDP when a heterotrimeric G protein is activated?
It hydrolyzes to GTP
What are the modes of internalization for GPCRs?
Clathrin-Coated Endocytosis and Caveolin Endocytosis
Which part of the Golgi Apparatus receives newly synthesized proteins?
$Cis$
What are RAMPs in relation to GPCRs?
Receptor Activity-Modifying Proteins, bind to GPCR and alter function
What are the types of signaling initiation for GPCRs?
Photoreceptors, odours/pheromones, Calcium, light, proteins (hormone)
Which domain of a GPCR constitutes the transmembrane portion?
Hydrophobic Lipophilic Domain
What are the subunits of a heterotrimeric G protein?
Alpha, beta, gamma
What are the methods of exiting Trans-Golgi Network (TGN)?
Constitutive secretion and regulated secretion
Which type of vesicles have many similarities to GSVs and are located in the pituitary gland to regulate the activity of the adrenal gland?
Regulated recycling vesicles
Which type of somatostatin receptors are internalized very quickly and recycle slowly?
sst2A
What is the pH range along the endocytotic pathway that allows lysosomes to degrade better and receptors to be separated from their ligands?
$4-5$
Which type of GPCR receptor has low affinity for visual arrestin and does not co-localize in endosomes?
Class A
What is the post-endocytic trafficking pathway of sst2A somatostatin receptors?
$ ext{Clathrin-coated vesicles} ightarrow ext{Endosomes} ightarrow ext{TGN} ightarrow ext{Cell surface}$
What is the effect of Brefeldin A on SSTR2 and syntaxin-6?
Does NOT affect SSTR2 or syntaxin-6
What happens when Class A GPCR receptors undergo ubiquitination?
RAPIDLY de-Ub, leading to fast recycling
What is the system that allows cells to adapt to environmental changes such as those in adipose tissue, muscle, and liver?
Regulated Recycling
What is the location of GSVLs?
Pituitary gland
Which type of GPCR receptor has high affinity for visual arrestin and co-localizes in endosomes?
Class B
Which RAMP binds to CLR, making it the receptor for AM1, a protein hormone with vasodilator effects?
RAMP2
What is the receptor for CGRP, a neuropeptide modulating pain transmission?
CLR binding to RAMP1
Which type of receptors require both wildtype isoforms for a functioning receptor at the cell surface?
GABAB receptors
How many groups of GRKs play a role in GPCR desensitization?
Three groups
What type of desensitization involves direct phosphorylation by GRK2, specific to the receptor?
Homologous desensitization
Which type of receptors prefer homologous desensitization due to more sites for GRK phosphorylation?
$\beta$2 adrenergic receptors
What is the structure of a GPCR?
Single transmembrane protein with N term in extracellular part and C term in intracellular
How many receptors within the GPCR SuperFamily have unknown function?
Over 600
What are the modes of internalization for GPCRs?
Clathrin-Coated Endocytosis and Caveolin Endocytosis
What is the effect of Brefeldin A on GPCR trafficking?
It inhibits vesicle formation at the TGN
What are RAMPs in relation to GPCRs?
They bind to GPCRs and alter their function
What is the role of Heterotrimeric G Proteins when activated?
GDP will hydrolyze to GTP, activating downstream signaling effectors
Which domain of a GPCR constitutes the transmembrane portion?
Hydrophobic Lipophilic Domain
What are the parts of Golgi Apparatus in sequence from receiving newly synthesized proteins to sending them to the plasma membrane?
Cis → Medial → Trans → PM
What are the types of signaling initiation for GPCRs?
Photoreceptors, odours/pheromones, Calcium, light, proteins (hormone)
Which type of receptors require both wildtype isoforms for a functioning receptor at the cell surface?
Class C GPCR receptors
Which GPCR-associated protein has four functions including chaperone, pharmacology switch, signaling switch, and trafficking switch?
RAMP
Which GPCR receptor is closely related to the calcitonin receptor (CTP) and interacts with RAMPs?
CLR (calcitonin-like receptor)
Which GPCR-associated protein is brought to the receptor by arrestin and stops GPCR signaling?
PDE4
Which type of GPCR desensitization involves four steps and three groups of GRKs?
Heterologous desensitization
Which type of somatostatin receptors exhibit different internalization and externalization responses?
$sst2A$ and $sst5$ receptors
What is the widespread location of GABAB receptor in the body?
Central Nervous System (CNS)
What are the two isoforms of the GABAB receptor?
GABAB1 and GABAB2
What are the two functions of arrestins in relation to GPCR desensitization?
Stopping signaling by binding to GPCR, direct binding to clathrin-coated pits
What is the enzyme that stops GPCR signaling by interacting with arrestin?
PDE4
What structure causes invaginations of the plasma membrane and is involved in GPCR internalization?
Caveolae
What is the pH range along the endocytotic pathway that allows lysosomes to degrade better and receptors to be separated from their ligands?
pH 4-5
Which type of GPCR receptor has low affinity for visual arrestin and does not co-localize in endosomes?
Class A
What is the post-endocytic trafficking pathway of sst2A somatostatin receptors?
Clathrin-coated vesicles -> Endosomes -> Trans-Golgi Network (TGN) -> Cell surface
What happens when Class A GPCR receptors undergo ubiquitination?
Rapid de-ubiquitination leading to fast recycling
What are GSVLs and where are they located?
GSV-like vesicles with many similarities to GSVs, located in the pituitary gland
Which type of somatostatin receptors are internalized very quickly and recycle slowly?
$sst2A$
What is the system that allows cells to adapt to environmental changes such as those in adipose tissue, muscle, and liver?
Regulated Recycling
Which type of GPCR receptor has high affinity for visual arrestin and co-localizes in endosomes?
Class B
What happens to GDP when a heterotrimeric G protein is activated?
It dissociates from the alpha subunit
What is the effect of Brefeldin A on SSTR2 and syntaxin-6?
Disperses Golgi around the cell but does not affect SSTR2 or syntaxin-6
Study Notes
Evolution and Functions of GPCRs and RAMPs
- RAMPs are highly conserved, with RAMP1 and RAMP3 being more closely related than RAMP2.
- RAMPs serve as chaperones, pharmacology switches, signaling switches, and trafficking switches for GPCRs.
- The calcitonin receptor (CTP) interacts with RAMPs and is closely related to CLR (calcitonin-like receptor).
- CLR binds to RAMP1 and becomes the receptor for CGRP, a neuropeptide modulating pain transmission.
- RAMP2 binds to CLR, making it the receptor for AM1, a protein hormone with vasodilator effects.
- RAMP3 binds to CLR, making it the receptor for AM2, a hormone regulating glucose levels.
- GABAB receptors, mediating rapid action ion channels, require both wildtype isoforms for a functioning receptor at the cell surface.
- GPCR desensitization involves a 4-step process: resting state, stimulation, phosphorylation, and desensitization.
- Three groups of GRKs play a role in GPCR desensitization, with different locations and domains.
- Homologous desensitization involves direct phosphorylation by GRK2, specific to the receptor, while heterologous desensitization involves second messenger kinases.
- Beta2 adrenergic receptors prefer homologous desensitization due to more sites for GRK phosphorylation.
- Arrestins are key adaptor proteins in GPCR desensitization and internalization, with four types and specific functions in stopping signaling and binding to GPCR.
Functions and Mechanisms of GPCR-Associated Proteins
- RAMPs, highly conserved, with RAMP1 and RAMP3 more closely related than RAMP2
- Four functions of RAMP: chaperone, pharmacology switch, signaling switch, trafficking switch
- Calcitonin receptor (CTP) interacts with RAMPs, closely related to CLR (calcitonin-like receptor)
- GABAB receptor, widespread in CNS, has two isoforms and a quality control mechanism
- sst2A and sst5, somatostatin receptors, exhibit different internalization and externalization responses
- Betanergic (B1) receptors extensively studied and used as GPCR model
- GPCR desensitization involves four steps and three groups of GRKs
- Homologous and heterologous desensitization of GPCRs, with beta2 adrenergic receptors preferring homologous desensitization
- Arrestins, key adaptor proteins in GPCR desensitization and internalization, have four types
- Arrestins have two functions: stopping signaling by binding to GPCR and direct binding to clathrin-coated pits
- PDE4, an enzyme brought to the receptor by arrestin, stops GPCR signaling
- Caveolae, formed by myelin, cause invaginations of the plasma membrane and are involved in GPCR internalization
Test your knowledge of G protein-coupled receptors (GPCRs) and heterotrimeric G proteins. Learn about the structure of GPCRs, the GPCR superfamily, hydrophobic and hydrophilic domains, and the types of signaling initiation. Explore the composition and activation of heterotrimeric G proteins.
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