Exam 2 General Info Flashcards
GABA-A orthosteric modulator
GABA
NMDA receptor orthosteric modulator
Glutamate / Glycine Site
GPCR orthosteric site
Can bind to many other drugs such a Z-hypnotics and other drugs on the sides. red and blue pieces passed around in class, compressed when an agonist binds, decompressed when unbound
GPCR terminuses
N outside of cell, C inside of cell
GPCR binding site?
In the transmembrane space close to the middle of the molecule
What is the G-protien complex made up of?
Alpha and Beta subunits & gamma
Nobel prize winners in 2012 for G-protein coupled receptors (possible EC)
Robert J. Lefkowitz and Brian K. Kobilka
Who discovered cyclic-amp and when? (This 100% EC he literally said in class)
Earl Wilbur Sutherland in 1971
What % of pharmaceutical drugs target GPCR
40%
How many classes of GPCR are there?
3 classes. A, B and C
Class A GPCR othersteric site is where? and where is the allosteric site?
Allosteric site is on the outside, orthosteric site is inside the receptor
Class B GPCR orthosteric site is where? and where is the allosteric site?
Allosteric is on the inside, orthosteric is on the top of the receptor
Class C GPCR orthosteric site is where? and where is the allosteric site?
“Venus fly trap” orthosteric site on top of the receptor, allosteric site inside the receptor like class A
Drug therapy in GPCR and where they try to bind?
Trying to find drugs that bind to allosteric sites of B and C because of the very similar structure and its hard to match “venus fly trap” orthosteric site.
Effectors of GPCRs
3 effectors, channels, enzymes and regulatory enzymes
Summary of G-proteins
receptor binds -> activates G-protein -> activated G-alpha or G-beta change the activity of an effector (usually an enzyme or an ion channel -> also changes the concentration which activates secondary messengers
Outcome of the G protein cycle
Alpha subunit starts off with a GDP but replaces it with a GTP when ligand binds to the receptor, and says fuck beta and runs away with GTP, cycle restarts when new alpha comes with GDP again
G-A-s (stimulatory) has 3 isoforms, what are they and what do they do?
g-alpha-s, g-alpha-s-XL (big bitch), g-alpha-olf (golf) they all stimulate adenylyl cyclases
G-A-I (inhibitory) what does it do?
inhibits adenylyl cyclases (has 7 isoforms) if we have to know them we should just die
G-A-q/11 ???? (who comes up with this stuff) wuts it do
it activates phospholipase C
G-A-12/13
recuit RHO guanine exchange factors (these help woth cell growth and cell shape
G-B-Y
5 beta and 12 gamma
what does adenylyl cyclase do?
converts ATP to cAMP dr watts loves these things + earl sutherland 👀👀👀👀 1971
how does cAMP exert its effects
through stimulating cAMP depended protein kinases (PKA)
where do irreversible antagonists bind? (allosteric site or orthosteric site?)
orthosteric site, this means the agonist will not be able to bind
what receptor subtype is likely to be involved with extremely fast drug response?
ion channels
what receptor subtype is likely to be involved with extremely slow drug response?
steriod receptors
how can we measure cAMP?
radioactive assays, protein-based biosensors-EPAC, fluorescent approach-HTRF
phospholipase C gets activated by G-q and what happens? (secondary messangers)
it produces phosphoinositides and diacylglycerol
cGMPs effector is what?
Guanyl cyclase
what does cGMP activate?
PKG (protein kinase G)
what is cGMP regulated by?
NO / NITRIC OXIDE
is cGMP specific?
yes, much more specific than other messenger proteins
What does viagra inhibit? (possible EC)
inhibits the breakdown of cGMP by phosphodiesterase 5 (PDE5)
what do kinases do?
add a phosphate (can increase or decrease activity)
what do phosphates do?
get rid of a phosphate (can increase or decrease activity)
After receptor activation there is a homologous desensitization (rapid desensitization) done by what?
GRK (G-protein receptor kinases)
What were GRK called initially? (possible EC)
B-ARK (woof)
After desensitization arrestin comes into the drug and decides 2 things, what are they?
Recycles the drug (dephosphoralation) or it degrades it (lysosomal degradation, TRASHED)
heterologous desensitization acts on multiple enzymes its non-agonist/receptor specific what can activate this?
PKA or PKC
what are the 3 functions of arrestin?
signaling, desensitization and endocytosis
what is agonist trafficking, biased agonism, ligand bias and differential engagement also called? (possible EC)
Functional selectivity
What does functional selectivity require?
For the receptor to couple to multiple signal transduction pathways
functional selectivity vs receptor selectivity
receptor selectivity is when the drug prefers a specific receptor while functional selectivity is once the drug has bound to the receptor it prefers a specific signaling pathway
whats eli lilly’s “blockbuster drug” which is functionally selective? (possible EC)
Tirzepatide
How functional selectivity can be used to design better drugs?
To induce one pathway such as B-arrestin when giving opioids to not get the bad side effects but keep the therapy. (ties in with HW2 about covid and Gq pathway and b-arrestin pathway
functional selectivity and opioids
b-arrestin causes GI issues and tolerance issues when activated by opioids, you want to induce that pathway and favor G protein pathway to get analgesia (try to create ligands that a selective to G-protein pathways)
Dr. Watts is currently studying functional selectivity with opioid receptors, which molecule is he targeting? (possible EC)
AC1 inhibitor adeylyl cyclase 1 (bypassing receptor and looking at specific pathways) (expressed primarily in the brain)
How do signaling mechanisms work?
transduce extracellular signals (drug) into extracellular messages (effect)
slowest types of receptors include these along with steroids
corticosteriods, mineralocorticoids, sex steriods, vitamin D and thyroid hormone
How do intercellular receptors work?
once bound it goes to the nucleus where it stimulates the transcription of gene by binding to specific DNA sequences
which of the 5 receptors can regulate gene transcription?
All of them, but they do them in different ways and different pathways
Protein tyrosine kinase pathway?
unliganded receptors with inactive tyrosine kinases get dimerized by EGF which phosphorylates the tyrosine kinase in the cell. 2 Grb2 proteins connect to the tyrosines and when Grb2 is near the cell surface it activated the Ras pathway which leads to transcription factors. Ras also has a lipid attachment keeping it on the cell membrane.
When the hormone binds to the extracellular receptor in protein tyrosine kinases when happens?
It goes through conformational change
How does protein tyrosine kinases turn off?
Usually, turn off themselves by down regulations, but upon ligand binding, another safety switch is endocytosis of the receptor.
what are some ligand-regulated transmembrane enzymes?
insulin, epidermal growth factors (ECF), and platlete derived growth factors (PDGF)
cytokine receptors and their pathway
cytokine binds and it causes kinases to come and attach to the intercellular part of the receptor. Once it becomes dimerized it then becomes phosphorated through the JAK molecules (tyrosine kinases molecules) the phosphorylated molecules then recruit stat which is dimerized to be able to express gene regulation.
cytokine storm is related to what?
Covid-19
what are the 5 types of receptors talked about in class?
intercellular receptor, extracellular, Phosphorylated (tyrosine & cytosines) ion channels and GPCRs
