Drug Receptors (Ch 2) Flashcards
list receptor type based on molecular structure
+ seven transmembrane (7TM) receptors
ex) GPCRs; 2/3 of all non-abx drugs bind to GPCRs
+ ligand-gated channels
+ ion channels
+ catalytic receptors
+ nuclear receptors
+ transporters
+ enzymes
describe the cell signaling process
- neuron releases neurotransmitters (signaling molecule – drug or endogenous ligand) from signaling cell
- signaling molecule (1st messenger) binds to receptor
- signal transduction proteins produce 2nd messengers
- 2nd messengers target effector protein to elicit effect (ex. cellular metabolism, function, movement etc.)
what types of drug processes will cause a lag period when regulating gene expression?
any processes that requires transcription/translation (protein production/mRNA)
how long is a lag period usually
30 min - several hours
what is drug persistence?
any drug that can be given once, but will remain in body for a long time
protein degradation pathways vary
how long can drug persistence be?
hours to days
what are the steps of a generic phosphorylation cascade?
- drug binds to receptor
- receptor confirmation change occurs
- inactive protein (kinase) becomes activated
- activated protein kinase 1 phosphorylates and takes protein kinase 2 and phosphorylates it (taking phosphate group from ATP, now making it ADP), thus becoming active
- effector activated > elicits effect
what is a kinase
any enzyme that attaches phosphate group to protein
Name 4 transmembrane signaling methods by which drug-receptor interactions exert their effects
- inTRAcellular receptors (lipid soluble/uncharged)
- ion channels
- catalytic receptors
+ receptor can become the enzyme itself inside the cell
+ activate a protein that activates subsequent enzymes (phosphorylation cascades) - GPCRs
+ receptor COUPLED to a second receptor (g-protein)
GPCR characteristics
G protein = guanine nucleotide (GTP) binding protein, which sets up the signaling process
activated receptor can activate 100s of g-proteins (multiplied response)
2/3 of all non-abx drugs
500 are identified, 500 orphans
fast response – metabotropic ion channels (also have rapid desensitization)
OR slow response – transcription factor activation (lag)
what is an orphan receptor?
no known endogenous ligand; roughly half of all receptors are identified
GPCR RECEPTOR (non-g protein) structure
receptor:
7TM (seven transmembrane) alpha helices (crosses membrane 7 times)
active site on outside of cell
inside the cell, site present to interact with g-protein
pleiotropy: several downstream effects possible
amino (NH3+) and carboxy (COO-) terminal ends
GPCR G-PROTEIN structure
trimeric: 3 subunits – amino acid strands (alpha, beta, gamma)
+ alpha most important (binds to GDP or GTP)
+ beta/gamma for binding to the receptor
GDP (inactive) turns into GTP (active)
list the steps for a generic GPCR signaling process
- drug binds to GPCR
- confirmation change occurs
- inactive GDP bound to alpha subunit gets replaced by activated GTP
- GTP + alpha subunit detach off g-protein and signal 2nd messengers
- second messengers activate effector protein to elicit effects
- alpha subunit + inactive GDP reattach to GPCR
what are some examples of second messengers
cGMP
calcium (released from cell storage)
DAG
most common:
cAMP
IP3
give an example of a g-protein and its second messenger and the effects it causes
G alpha-stimulatory class > adenylyl cyclase (effector) > cAMP increased > effector (B-adrenergic receptor (to increase HR/contractility)
G alpha-inhibitory class > adenylyl cyclase K+ channel (effector) > cAMP (decreased) > alpha adrenergic receptor/muscarinic ACh receptors (to decrease HR)
GPCR + cAMP
- 1st messenger attaches to GPCR
- GTP replaces GDP on alpha subunit
- GTP+Alpha sub attach to effector protein
- adenylyl cyclase converts ATP to cAMP and cAMP levels increase
- cAMP becomes 2nd messenger and activates protein kinase A
- protein kinase A starts phosphorylation cascade of other proteins
- cellular responses are elicited
describe the structure of RTKs
outer membrane bound receptor site where ligand binds and activates
in the cytoplasmic catalytic domain, receptor has:
+ tyrosine kinase (amino acid enzyme that attaches phosphate groups)
+ once dimerization occurs (two monomers fuse), tyrosine kinase becomes phosphorylated
what do second messengers do?
second messengers signal the target protein to elicit downstream effects, which in turn will elicit cellular responses
define desensitization in GPCRs
if an agonist is bound for a long period of time (i.e. covalently bonded), the GPCR can mute the prolonged drug response over time by using a process called desensitization
define beta arrestin’s role in GPCR desensitization
- GPCR with ligand bound goes from closed conformation to open conformation
- the open conformation of the receptor has 3 -OH groups at the terminal end inside the cytoplasm which get phosphorylated and the alpha subunit binds becomes activated by binding with GTP and starts the signaling cascade
- if the receptor remains in its open conformation for a long period of time (which may be due to the drug being covalently bound), beta arrestin binds to the terminal end of the receptor with the now phosphorylated groups
- beta arrestin ARRESTS the signaling cascade, then interacts with the clatherin coated pit, which is involved in endocytosis
- the clatherin coated pit endocytoses the receptor, ligand, and beta arrestin
two possible outcomes may follow:
a. the drug may become unbound from the receptor and the receptor wil be dephosphorylated by proteases and can be “recycled” back into the cell membrane
b. a lysosome and the endosome merge and break down the receptor/drug
what is tyrosine phophatase?
an enzyme that strips phosphate from a protein
list the steps of receptor tyrosine kinase signal transduction
- two monomer RTKs bind to their respective ligands
- dimerization occurs
- phosphorylation of RTKs occurs via ATP
- effector proteins signaled and downstream effects occur
what is the difference between ligand gated vs voltage gated ion channels?
ligand gated:
+more common
+ionotropic
+ligand binding site and channel on the same protein
+nACh receptor
voltage gated:
+found in excitable cells (neurons, muscle, endocrine cells)
+closed at resting membrane potential (the baseline charge on membrane until the threshold is met)
+types based on ion selectivity (Ca2+, K+, Na+)
+regulated by physical “gates”
ionotropic ligand gated ion channels
more common
ligand binding site and channel on same protein
ex) nicotinic/ACh receptor found on surface of skeletal muscle
metabotropic ligand gated ion channel
more complicated
ligand activates GPCR
second messenger activity opens the channel
ex) odorant receptor
list the types of ligands that can bind to receptors INSIDE the cell
gasses (NO)
lipid soluble agents (steroids)
