PHA 340: Pharmacodynamics (part II)
G-protein Coupled Receptors (GPCRs) are also known as
- Metabotropic receptors
- 7 transmembrane receptors
- Serpentine receptors
What are the 3 major components of a GPCR system?
- G protein
- Effector molecule
In the basal/resting state, a G protein is composed of what subunits?
trimer of α, β, γ subunits.
The _________ in a GPCR system is acted upon (regulated) by the G protein.
True/False: The GPCR receptor is a single polypeptide chain
In a GPCR, the G-protein interacts with which cytoplasmic loops of the the receptor?
2nd or 3rd
True/False: In GPCR, activated G-protein interacts with an effector (i.e. ion channel, enzyme) that alters intracellular process.
In basal/resting state of GPCR, GDP is bound to which subunit?
In GPCR, what happens when the receptor is occupied?
- Ligand binds to receptor causing conformational change to receptor
- GDP/GTP exchange in α subunit of G-protein
In GPCR, what happens when the receptor is in an active state?
- α-GTP complex dissociates, active G-protein
- α-GTP complex binds to effector molecules
- β γ subunits can also act on effectors
- Leads to signal amplification
______________ is when single ligand-receptor complex activates many G-proteins and G-proteins can activate many effectors
Signal amplification (i.e. "promiscuous")
What happens during the terminal state of GPCR?
- GTP hydrolyzed to GDP, inactivates α-GTP
- Complex dissociates from effector molecule
- Subunits reassociate
This G protein stimulates activity of adenylyl cyclase (i.e. β-adrenergic receptors)
This G protein inhibits activity of adenylyl cyclase, leading to decrease of cAMP in cell (i.e. Dopamine D2 receptors)
This G protein stimulates activity of phospholipase C (i.e. Muscarinic M1 and M3 receptors, α1-adrenergic receptors)
In a cAMP signaling pathway, cAMP is considered a _____ (1st/2nd) messenger that activates protein kinases.
What do protein kinases do?
In a cAMP signaling pathway, what does the agonist bind to?
When a G-protein becomes activated in a cAMP signaling pathway, it increases the amount of ________
Adenylyl cyclase (AC) produces _______
In a cAMP signaling pathway, cAMP activates what protein kinase by binding to R2 subunits
In a cAMP signaling pathway, activated C2 phosphorylates __________
In a cAMP signaling pathway, what carries out the response?
Phosphorylated target protein
What is an example of a drug that uses a cAMP signaling pathway?
In a PLC signaling pathway, the agonist binds to _______
In a PLC signaling pathway, the activated G-protein increases ______
In a PLC signaling pathway, PLC cleaves _______ into DAG and IP3
In a PLC signaling pathway, DAG activates _____
In a PLC signaling pathway, _____ triggers the release of intracellular Ca2+
In a PLC signaling pathway, Ca2+ binds to _______________ which influences activity of protein kinases and other enzymes
What is an example of a drug that uses a PLC signaling pathway?
What does Pilocarpine do?
Allows contraction of ciliary muscles to cause outflow of aqueous humor and a reduction in intraocular pressure (used for glaucoma)
Examples of enzymes as receptors
- Tyrosine kinase
- Serine kinase
- Guanylyl cyclase
Example of receptor linked to enzyme
What is the general activation process of an enzyme linked receptor?
- Ligand binds to receptors
- Dimerization of receptors
- Autophosphorylation / cross phosphorylation of receptors
- Phosphorylation of target intracellular protein
What is an example of a ligand that binds to the enzyme linked receptor, tyrosine kinase?
Epidermal Growth Factor (EGF)
True/False: Tyrosine kinase is an example of an enzyme linked receptor that utilizes the kinase/phosphorylation cascade to decreases gene transcription.
True/False: Cytokine receptors do not have catalytic activity.
Cytokine receptors are bound to an intracellular enzyme, ______, that will activate once the agonist molecules bind and form a dimer.
JAK phosphorylates ________ (after binding to receptors) causing them to then dimerize and regulate gene transcription.
What is an example of a compound that uses cytokine receptors?
Erythropoietin (in bone marrow)
How many molecules of erythropoietin are required to activate the EPO receptors (cause dimerization)?
The binding of EPO would ultimately cause what systemic response?
Increase in growth and maturation of RBCs
Where are nuclear receptors located and what do they do?
Intracellular; regulate transcription of genes
True/False: The effects brought on by activation of nuclear receptors usually do not take longer than those brought on by voltage gated ion channels.
Examples of endogenous ligands and drugs utilizing nuclear receptors
- Sex steroids
- Thyroid hormone
What are the 3 domains of Nuclear receptors?
- C terminus
- Central region
- N terminus
This domain of a nuclear receptor is the ligand binding domain and the binding area for co-regulators
This domain of a nuclear receptor is the DNA binding domain where the zinc fingers are located (Zn bound to 4 cys residues)
This domain of a nuclear receptor is the transcription regulating domain
What is the activation process for nuclear receptors?
- Binding of agonist
- Dimerization of receptors
- Dimer binds to DNA
- Regulation of gene transcription
Prevents the active conformation of receptor when ligand is absent (associated w/ nuclear receptors)
hsp90: Heat shock protein
What type of receptor is the glucocorticoid receptor classified as?
Which of the following ligands acts on cytokine receptors? Select ALL that apply.
- Epidermal growth factor