G Protein-Coupled Receptors Overview

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Questions and Answers

What is a primary function of adaptor proteins in relation to RTKs?

They directly activate GTPase proteins.

They enable two or more signaling proteins to connect. (correct)

They act as enzymes that phosphorylate RTKs.

They help in the internalization of RTKs.

Which domain do docking proteins typically contain that allows interaction with RTKs?

SH3 domain

ZF domain

PTB domain or SH2 domain (correct)

PDZ domain

What role do the enzymes associated with RTKs typically play?

They sequester RTKs from cellular membranes.

They activate RTKs by supplying them with inorganic phosphates.

They amplify the signals from activated RTKs. (correct)

They process phosphorylated RTKs for degradation.

How is the signal transduction process by RTKs primarily terminated?

Through the internalization of the RTKs. Signup and view all the answers

Which enzymes are mentioned as needing inorganic phosphates derived from ATP?

Protein kinases and protein phosphatases Signup and view all the answers

What is the role of phosphorylation in the signaling process?

It facilitates receptor activation and downstream signaling. Signup and view all the answers

What does dimerization of receptors typically involve?

Interactions between activated receptor pairs. Signup and view all the answers

Which type of proteins are typically recruited to the phosphorylated tyrosine residues?

Proteins with SH2 or PTB domains. Signup and view all the answers

What is the function of the STAT family of transcription factors after phosphorylation?

They form dimers to stimulate transcription of specific genes. Signup and view all the answers

What is necessary for the activation of STAT proteins?

Phosphorylation by receptor kinases. Signup and view all the answers

What initiates the interaction between two STAT proteins?

Phosphorylated tyrosine residues on one STAT protein binding to the SH2 domain of another. Signup and view all the answers

How are receptor protein-tyrosine kinases (RTKs) activated?

Through autophosphorylation on tyrosine residues. Signup and view all the answers

What is the consequence of forming signaling complexes after RTK activation?

Binding of SH2 or PTB domain-containing proteins to initiate signaling. Signup and view all the answers

What role does arrestin play in relation to GPCRs?

It competes with the active site to prevent overstimulation. Signup and view all the answers

Which of the following is NOT a second messenger derived from membrane phospholipids?

Glucose Signup and view all the answers

Which enzyme is NOT directly involved in converting membrane phospholipids into second messengers?

Adenylyl cyclase Signup and view all the answers

What is the primary function of regulators of G protein signaling (RGSs)?

To increase the rate of GTP hydrolysis by G subunits. Signup and view all the answers

What evolutionary characteristic is noted regarding G proteins?

Their signaling mechanism is of ancient origin and highly conserved. Signup and view all the answers

What effect do mutations in GPCRs typically have on cellular function?

They cause the cellular response to malfunction. Signup and view all the answers

Which of the following statements about Gα subunits is FALSE?

Gα subunits are not involved in GPCR signaling. Signup and view all the answers

Which of the following is known as a primary messenger in cellular signaling?

Nitric oxide Signup and view all the answers

What role does receptor-binding protein Cbl play in relation to activated RTK receptors?

It catalyzes the attachment of a ubiquitin molecule. Signup and view all the answers

Which of the following is NOT a fate of internalized GPCRs and RTKs?

Transformation into transcription factors Signup and view all the answers

What is the effect of GTPase-activating proteins (GAPs) on Ras protein function?

Promotes GTP hydrolysis Signup and view all the answers

How does Ras protein become activated?

By exchanging GDP for GTP Signup and view all the answers

What is the primary function of ubiquitin in cellular processes?

To mark proteins for degradation or internalization Signup and view all the answers

Which of the following correctly describes a feature of the Ras protein?

It functions similarly to heterotrimeric G proteins. Signup and view all the answers

What is the role of guanine nucleotide-dissociation inhibitors (GDIs) in relation to GDP?

They inhibit the release of bound GDP. Signup and view all the answers

What initiates the hydrolysis process of GTP in Ras protein signaling?

Association with GAP Signup and view all the answers

What phenomenon describes the interaction between different signaling pathways, allowing signals to be exchanged?

Cross-talk Signup and view all the answers

Which of the following best explains the process where signals from the same ligand activate different pathways?

Divergence Signup and view all the answers

Which common effector can be activated by signals from a variety of unrelated receptors?

Ras Signup and view all the answers

What role does cyclic AMP play in the signal transduction pathway?

It acts as a secondary messenger and activates PKA. Signup and view all the answers

How do PKA and the kinases of the MAP kinase cascade interact with the transcription factor CREB?

They phosphorylate CREB on the same serine residue, activating it. Signup and view all the answers

Study Notes

G Protein-Coupled Receptors (GPCRs)

GPCRs are cell surface receptors that bind to a variety of ligands, including hormones, neurotransmitters, and light.
Upon ligand binding, GPCRs activate a signal transduction pathway that involves the heterotrimeric G protein.
G proteins are composed of three subunits: α, β, and γ.
In the inactive state, the Gα subunit binds to GDP.
Upon activation, the Gα subunit exchanges GDP for GTP and dissociates from the βγ subunits.
The activated Gα subunit and βγ subunits interact with downstream effector proteins, leading to a variety of cellular responses.

Important Notes on GPCRs

Gα subunits possess weak GTPase activity, which allows them to slowly hydrolyze the bound GTP and inactivate themselves.
Termination of the response is accelerated by regulators of G protein signaling (RGSs), which increase the rate of GTP hydrolysis by the G subunit.
The mechanism for transmitting signals across the plasma membrane by G proteins is of ancient evolutionary origin and is highly conserved.
One-third of all prescription drugs act as ligands that bind to GPCRs, and a number of inherited disorders affect GPCRs.
Mutations in the GPCR usually affect the cascade of signals from the outside of the cells to the intracellular components; therefore, the cell fails to act or produce molecules accordingly.

Second Messengers

Second messengers are small intracellular molecules that relay signals from activated receptors to downstream targets.
Second messengers are produced in response to the activation of cell surface receptors.
Play an essential role in signal transduction by altering the activity of target proteins and initiating changes in cell behaviour.
Examples of second messengers include:
- cAMP
- Diacylglycerol
- Inositol triphosphate (IP3)
- Ca2+
- cGMP

Phosphatidyl Inositol Derived Second Messengers

Membrane phospholipids are converted into second messengers by a variety of enzymes:
- Phospholipases
- Phospholipid kinases
- Phospholipid phosphatases
Inositol-containing lipids can be phosphorylated by specific lipid kinases that are activated in response to extracellular messenger molecules, such as acetylcholine.

Examples of Second Messengers

Inositol 1,4,5 trisphosphate (IP3) is a sugar phosphate - a small, water-soluble molecule capable of rapid diffusion throughout the interior of the cell. It plays a crucial role in calcium signaling by binding to and opening calcium channels on the endoplasmic reticulum (ER) membrane, releasing calcium into the cytoplasm.

Receptor Tyrosine Kinases (RTKs)

RTKs are cell surface receptors that possess intrinsic tyrosine kinase activity.
They play crucial roles in regulating numerous cellular processes like cell growth, differentiation, metabolism, and survival.
Upon ligand binding, RTKs undergo dimerization and autophosphorylation.

Activation of Downstream Signaling Pathways

Autophosphorylation of RTKs creates docking sites for downstream signaling proteins containing SH2 or PTB domains.
These binding events initiate a cascade of signaling events leading to changes in gene expression, cell growth, and other cellular processes.
The signaling pathway triggered by RTK activation varies depending on the specific receptor and the cell type.

Adaptor Proteins and RTKs

Adaptor proteins act as linkers that enable two or more signaling proteins to become joined together as part of a signaling complex.
Adaptor proteins contain an SH2 domain and one or more additional protein-protein interaction domains.

Docking Proteins and RTKs

Docking proteins contain either a PTB domain/SH2 domain and a number of tyrosine phosphorylation sites.
They function as scaffolding proteins, bringing together signaling molecules and facilitating the formation of signaling complexes.
This organized assembly promotes efficient signal transduction, enabling specific responses to different stimuli.

Transcription Factors and RTKs

They usually involve the STAT family, requiring phosphorylation to be activated.
STATs contain an SH2 domain together with a tyrosine phosphorylation site that can act as a binding site for another SH2 Stat molecule.
STATs are activated by phosphorylation on tyrosine residues, a process typically initiated by RTKs.
Upon RTK interaction, tyrosine residues in these STAT proteins are phosphorylated, initiating the interaction between the phosphorylated tyrosine residue on one STAT protein and the SH2 domain on a second STAT protein, and vice versa.
Once phosphorylated, STATs dimerize and translocate to the nucleus, where they act as transcription factors, regulating gene expression involved in a variety of cellular processes, including immune responses, growth, and development.

Signaling Enzymes and RTKs

Enzymes can directly interact with the inorganic phosphate found in RTKs.
Enzymes usually need inorganic phosphates that they derived from ATP.
Examples of signaling enzymes that interact with RTKs include protein kinases, protein phosphatases, lipid kinases, phospholipases, and GTPase activating proteins.
If enzymes have SH2 domains, these enzymes associate with activated RTK and are turned on directly or indirectly.

Important Notes on Protein-Tyrosine Phosphorylation

Signal transduction by RTKs is usually terminated by internalization of the receptor.
Receptor-binding protein Cbl possesses an SH2 domain hence it will associate with the active RTK receptor and later on catalyzes the attachment of a ubiquitin molecule to the receptor.
Ubiquitin is a small protein that is linked covalently to other proteins, thereby marking those proteins for internalization or degradation.
Binding of the CBl complex to activated receptors is followed by receptor ubiquitination and internalization.
GPCRs, internalized RTKs can have several alternate fates; they can be degraded in lysosomes, returned to the plasma membrane, or become part of endosomal signaling complexes and engage in continued intracellular signaling.
Transfer of energy from messenger which is phosphorylation or inorganic phosphate. Conversion of ATP to ADP for energy.

G Protein Cycle

G proteins cycle between an active GTP-bound state and an inactive GDP-bound state.
This cycle is regulated by the interaction of G proteins with accessory proteins:
- GTPase-activating proteins (GAPs) stimulate GTP hydrolysis, promoting the inactive GDP-bound state.
- Guanine nucleotide-exchange factors (GEFs) stimulate dissociation of GDP, favoring the active GTP-bound state.
- Guanine nucleotide-dissociation inhibitors (GDIs) inhibit the release of a bound GDP, keeping the G protein in its inactive state.

Ras Map-Kinase Pathway

The Ras-MAP kinase pathway is a signaling cascade that plays a crucial role in regulating cell growth, differentiation, and survival.
It is a highly conserved pathway found in most eukaryotes and is frequently deregulated in cancer.

Ras Protein

Ras is a small GTPase that is anchored at the inner surface of the plasma membrane by a covalently attached lipid group.
It exists in an active and inactive GDP-bound form.
Ras-GTP activates downstream signaling proteins; turned off by hydrolysis of GTP.

Convergence, Divergence, and Cross-Talk

Convergence: Signals from a variety of unrelated receptors, each binding to its own ligand, can converge to activate a common effector, such as Ras or Raf.
Divergence: Signals from the same ligand, such as EGF or insulin, can diverge to activate a variety of different effectors and pathways, leading to diverse cellular responses.
Cross-talk: Signals can be passed back and forth between different pathways, a phenomenon known as cross-talk, allowing for complex integration and coordination of cellular responses.

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Description

This quiz focuses on G Protein-Coupled Receptors (GPCRs), detailing their structure, function, and the mechanisms involved in signal transduction. It covers the roles of G proteins and the activation process leading to cellular responses. Test your understanding of these essential cellular components and their signaling pathways.