Pharmacodynamics - Receptor types Flashcards
What are drugs designed to target?
Regulatory proteins in existing cell signaling pathways
What are 5 major classes of drug targets?
Membrane receptors Nuclear receptors Ion channels Transport proteins Enzymes
In an inactive state, describe the setup of a GPCR
alpha subunit bound to GDP, as well as to the beta and gamma subunits
Once the ligand binds the GPCR it is converted to its active state. Describe the setup
Alpha subunit dissociates from the beta and gamma subunits and binds GTP
What subunit of the GPCR contains the gtpase activity?
Alpha subunit
Gs
Activates Adenylyl Cyclase
Gi
Inhibits Adenylyl cyclase
Gq
Activates PLC
G12/13
Activates RHO GTPases which then activates cytoskeleton rearrangements
G proteins are classified based on?
Alpha subunit induced effects
What occurs if the GPCR is active for a continued amount of time?
Desensitization = DECREASED cAMP
If the agonist is removed quickly from the GPCR what will occur?
Resensitization - full response to a second agonist
If downregulation occurs, where is the GPCR delivered?
Lysosomes
What are the 3 new players in GPCR resensitization?
GRK
Beta-arrestin
Protein Phosphatase
Describe how GPCR resensitization occurs
- GRK phosphorylates GPCR and prevents it from interacting with Gs
- Beta-arrestin binds the phosphorylated GPCR
- Beta-arrestin - GPCR complex binds to coated pits and is internalized
- Agonist dissociated from GPCR = decreased beta-arrestin affinity
- Protein Phosphatase dephosphorylates GPCR
- GPCR returned to plasma membrane
Gs activates Adenylyl Cyclase. What does AC activate?
cAMP
What hydrolyzes cAMP?
PDE
Gq activates PLC. PLC then activates?
PIP2
- IP3 and DAG
JAKs
Janus Kinases
What types of ligands will activate JAK-STAT pathway?
Hormones and Cytokines
When a cytokine binds to its receptor, JAKs are activated. What do JAKs do?
Phosphorylate and activate STATs
Once 2 STATs are activated and phosphorylated by JAKs, what occurs?
They form a dimer and move to the nucleus to alter transcription
When the JAK-STAT pathway is ON, what diseases occur?
Excessive inflammation
Autoimmune diseases
What 3 things can JAK-STAT pathway INHIBITORS help control?
Rheumatoid Arthritis
Psoriasis
Inflammatory Bowel Disease
Describe the JAK-STAT pathway
Cytokine binds to receptor
JAKs activated
JAKs phosphorylate and activate STATs
STATs form dimers
STATs go to nucleus and alter transcription
= Control immune-mediated inflammatory diseases
What ligands bind to Receptor Tyrosine Kinases?
GROWTH HORMONES
“GF”
Growth Hormones bind?
Receptor Tyrosine Kinases
Once 2 Growth Hormones bind a RTK at 2 locations, what happens?
2 RTKs will join to form a dimer = ACTIVE
Once RTKs form a dimer, what happens?
Auto-phosphorylation of tyrosine residues
Once Tyrosine residues are auto-phosphorylated, what occurs?
Their enzymatic activities are activated and they can phosphorylate other substrates
What receptors are involved with RAS?
Receptor Tyrosine Kinases
growth hormones
How is RAS activated?
- An adaptor protein binds to the phosphorylated tyrosine residues
- A RAS activating protein binds to the adaptor protein and activates RAS GTPase
- RAS is then bound to GTP and is active
RAS activates?
Raf
MEK
ERK
= cell cycle overstimulated
Oncogenes often affect what type of receptor?
Receptor Tyrosine Kinases – RAS pathway
Nuclear receptors modulate?
Gene expression
Ligands that bind to nuclear receptors must be ____
Lipophilic
What type of ligands bind to nuclear receptors?
Steroids and hormones and Vitamins
Nuclear receptors have a ligand binding domain, dna binding domain and transcription activating domain. What binds to the receptor in absence of a ligand to inactivate it?
Heat Shock protein 90 (HSP90)
What causes the HSP90 to dissociate from the nuclear (glucocorticoid) receptor?
Binding of a ligand
Glucocorticoid nuclear receptor activation causes?
Transrepression of NF-KB and AP-1
Verapamil is an example of a drug that targets?
L-type calcium channels
