MODULE 7: Chapter 8.2 Flashcards
What are G protein–coupled receptors (GPCRs)?
A large number of receptors involved in sensory perceptions such as vision, taste, and smell
GPCRs have an evolutionarily conserved structure with seven transmembrane α helices.
What is the structural orientation of GPCRs?
The amino terminus is oriented towards the extracellular space, and the carboxyl terminus is exposed to the cytosol.
What is the significance of the term ‘serpentine receptors’?
It refers to GPCRs due to their snake-like structure formed by seven transmembrane α helices.
What role does the N-terminal domain of GPCRs play?
It often contains one or more carbohydrate functional groups.
What is the function of adenylate cyclase (AC) in GPCR signaling?
Produces cAMP.
What does the β2-adrenergic receptor (β2-AR) bind to?
Binds epinephrine.
What is the role of β-adrenergic receptor kinase (βARK)?
Acts on β-adrenergic receptors as a specific G protein–coupled receptor kinase.
What is the function of phosphodiesterase (PDE)?
Breaks down cAMP or cGMP.
What does Gα represent in GPCR signaling?
A G protein subunit.
What is the role of GTPase activating protein (GAP)?
Stimulates GTPase activity of G proteins to inhibit signaling.
What is the function of guanine nucleotide exchange factor (GEF)?
Promotes GDP–GTP exchange to activate signaling.
What is the significance of rhodopsin in GPCRs?
It was the first GPCR analyzed at the molecular level and contains a bound retinal molecule that absorbs light.
What causes conformational changes in GPCRs?
Ligand binding on the extracellular side of the receptor.
What are the three steps in G protein–coupled receptor signaling?
- Ligand-induced conformational changes in the GPCR and binding of the inactive heterotrimeric G protein
- Receptor-mediated stimulation of guanine nucleotide exchange in the Gα subunit
- Regulation of downstream effector processes by Gα–GTP and Gβγ complexes.
What does the Gα subunit do in the inactive state?
Contains GDP bound and associates with the GPCR after receptor activation.
How many different Gαβγ complexes can theoretically form in humans?
Approximately 1000 different complexes.
What second messenger does Gsα stimulate?
cAMP.
What is the role of Gqα?
Activates phospholipase C to generate DAG and IP3.
What do GPCRs regulate in sensory perception?
Intracellular levels of second messengers.
What hormones regulate glycogen degradation in liver cells?
- Glucagon
- Epinephrine.
What type of signaling pathways do glucagon and epinephrine activate?
Shared and parallel downstream signaling pathways.
How does glucagon signal in liver cells?
Binds to glucagon receptors and activates Gsα signaling to produce cAMP.
What receptors does epinephrine bind to in liver cells?
- β2-adrenergic receptors
- α1-adrenergic receptors.
What is the physiological role of glucagon?
Released in response to low blood glucose levels.
What class of first messengers does epinephrine belong to?
Catecholamines.
What type of proteins do glucagon and epinephrine activate in liver cells?
Gα proteins (Gsα or Gqα)
This activation leads to parallel signaling pathways.
What is glucagon?
A peptide hormone released by the pancreas in response to low blood glucose levels.
Where are glucagon receptors primarily expressed?
Liver and adipocyte cells.
Why is epinephrine sometimes called the ‘fight or flight’ hormone?
It is released from the adrenal medulla under times of acute stress.
What are the physiological effects of epinephrine?
Increased heart rate and mobilization of energy stores through glycogen breakdown and lipolysis.
What types of adrenergic receptors do catecholamines bind to?
α-adrenergic and β-adrenergic receptors.
What is the function of adrenergic receptor agonists?
Activate receptor signaling by mimicking natural ligands.
What do adrenergic receptor antagonists do?
Bind to receptors with high affinity and block the binding of physiological agonists.
What is clonidine used for?
Treatment of high blood pressure and insomnia.
What is the role of isoproterenol?
A potent β2 agonist used by asthmatics to relax smooth muscle in the lungs.
Name an example of a β1-adrenergic receptor antagonist.
Metoprolol.
What is the primary role of Gsα in signal transduction?
Facilitates binding to adenylate cyclase.
What conformational change occurs in Gsα upon GTP binding?
Switch II helix region changes to interact with adenylate cyclase.
What does PKA stand for?
Protein kinase A.
What is the structure of inactive PKA?
R2C2 tetramer consisting of two regulatory subunits and two catalytic subunits.
What triggers the activation of PKA?
Binding of cAMP to the regulatory subunits.
What is a pseudosubstrate sequence?
A sequence in the regulatory subunit that mimics the substrate sequence recognized by the catalytic domain.
What does the binding of cAMP to the regulatory subunits cause?
Dissociation of the regulatory and catalytic subunits.
What are the three distinct metabolic responses activated by PKA in liver cells?
- Phosphorylation and inhibition of glycogen synthase
- Phosphorylation and activation of enzymes for glycogen degradation
- Phosphorylation and activation of enzymes for gluconeogenesis.
What is the effect of cAMP phosphodiesterase?
Hydrolyzes cAMP to AMP, modulating its steady-state levels.
What second messengers are generated by the hydrolysis of PIP2?
- DAG
- IP3.
What does DAG activate?
Protein kinase C (PKC).
What does IP3 stimulate?
Ca2⁺ release from the endoplasmic reticulum.
What is the G protein cycle?
Sequential stimulation of G protein signaling by GEF activity followed by activation of GTPase activity by GAPs.
What is the role of GEF proteins?
Promote GDP–GTP exchange and activate signaling.
What do GAPs do?
Stimulate the intrinsic GTP hydrolyzing activity of G proteins.
What is the function of RGS proteins?
Regulate G protein signaling by stimulating GTPase activity.
What is the role of G protein–coupled receptor kinases (GRKs)?
Phosphorylate GPCRs to mark them for recycling.
What is βARK?
A specific type of GRK associated with β2-adrenergic receptors.
What does β-arrestin do?
Binds to phosphorylated receptors and prevents reassociation with Gαβγ complex.
How does receptor desensitization occur?
Through phosphorylation of the GPCR cytoplasmic domain, marking it for recycling.
What is the role of coupled receptor kinase in GPCR signaling?
Provides a docking site for β-arrestin, preventing reassociation with Gαβγ complex.
How is GPCR signaling terminated?
By recycling receptors through endocytic vesicles after ligand activation.
What proteins phosphorylate the GPCR cytoplasmic tail?
G protein–coupled receptor kinase proteins, such as βARK.
What does β-arrestin do in the context of GPCR signaling?
Binds to the phosphorylated receptor and facilitates its transport to endosomal compartments.
What happens to GPCR after dephosphorylation in endocytic vesicles?
It is either degraded or returned to the plasma membrane.
What is feedback inhibition in GPCR signaling?
Phosphorylation of GPCRs by downstream kinases like PKA, which affects receptor activity.
What are the two domains of β-arrestin responsible for?
Recognizing phosphoserine and phosphothreonine residues on target proteins.
What class of responses do most human GPCR genes account for?
Sensory perception (vision, smell, taste).
How many G protein genes are encoded in the human genome?
17 Gα, 5 Gβ, and 12 Gγ genes.
Why are fewer heterotrimeric G protein genes needed?
Selectivity of signal transduction depends on the receptor, not the signaling mechanism.
What is rhodopsin?
A GPCR consisting of seven α helices and a bound retinal molecule that absorbs light.
What is a heterotrimeric G protein?
A membrane-bound protein complex associated with GPCRs that dissociates upon receptor ligand binding.
What is the function of GTPase?
Cleaves GTP to form GDP plus inorganic phosphate.
What does glucagon signal?
Low glucose levels in the blood.
What are catecholamines?
A class of first messenger hormones derived from tyrosine.
What is a receptor agonist?
A compound that binds and activates a receptor protein.
What is a receptor antagonist?
A compound that blocks receptor activation by preventing binding of the natural ligand.
What is the role of protein kinase A (PKA)?
Activates numerous target proteins and enzymes in the cAMP signaling pathway.
What is a guanine nucleotide exchange factor (GEF)?
A protein that promotes GDP–GTP exchange and activates signaling.
What does the G protein cycle involve?
Sequential stimulation by GEF activity and activation of GTPase activity by GAPs.
What is β-adrenergic receptor kinase (βARK)?
A kinase that phosphorylates the β2-adrenergic receptor to terminate its signal.
What is the function of GTPase activating protein (GAP)?
Stimulates the intrinsic GTP hydrolyzing activity of G proteins.
What is the role of G protein–coupled receptor kinase (GRK)?
Phosphorylates the GPCR cytoplasmic domain, marking it for recycling.
