Lecture 3: Pharmacodynamics Part 2 Flashcards
t/f all receptors exhibit similar basic principles wrt their interactions with drugs
true
there are __ primary classes of receptors
4
what are the 4 primary classes of receptors?
- intracellular receptors
- enzyme-linked receptors
- ligand gated ion channels
- GPCRs
the intracellular class of receptors is sometimes further subdivided for receptors that remain in the __. These are called __
nucleus; intranuclear receptors
what is unique about intracellular class receptors?
the ligands acting on them must enter the cell in order to have their effect
enzyme-linked receptors can be divided into what 2 categories?
- receptors that have enzymatic site as part of the receptor itself
- receptors that are associated with intracellular enzymes
in enzyme-linked receptors, activation of receptor causes __
increased activity of an enzyme
what are ligand gated ion channels?
membrane channels that allow passage of ions based on binding ion ligand
what are G protein coupled receptors?
large proteins characterized by 7 transmembrane spanning domains
in a GPCR, the intracellular domain associates with a __, which when activated will initiate a series of __ to cases a cellular response
G protein complex; cellular events
most drugs that bind to intracellular receptors are __ soluble. why is this?
fat. to cross the lipid membrane
when activated, intracellular receptors do what 3 things?
. Interact with gene response elements on DNA and modulate gene transcription, resulting in changes in protein synthesis
what is the time frame of intracellular receptor drugs to have aparent effects?
several hours to days
why does it take so long for intarcellaulr receptor drugs to take effect?
processes of receptor stimulation to protein synthesis takes a significant amount of time
explain the structure of enzyme linked receptors
2 transmembrane spanning units with ligand binding sites the extracellular domains
what happens to the 2 subunits of an enzyme linked receptor when a ligand binds?
the 2 subunits associate together to initiate enzymatic activity within the cell
give an example of an enzyme linked receptor that associates with intracellular tyrosine kinase enzymes
interleukin 2 (iL 2)
the epidermal growth factor is an example of a ___ type receptor, which contains ___ as part of the intracellular parts of the receptor itself
tyrosine kinase; enzymatic domains
the associated / “built in” tyrosine kinase domains initiate ___ when receptor is activated
intracellular signalling cascade
when 2 receptor subunits associate, they become __ in relation to each other and this allows them to _____, which is called ___
closer; phosphorylate each other; autophosphorylation
what is the role of autophosphorylation of 2 receptor subunits?
activates enzymatic activity and initiates the downstream signalling response in the cell
what is it called when two receptor subunits associate?
dimerization
give an example of ligand gated ion channels
nicotinic acetylcholine receptors
ligand gated ion channels contain a ___ that when opened allows the flow of ions across the membrane
transmembrane pore
where can ligand gated ion channels be found in the body?
in neurons and muscle cells
binding of a ligand to a ligand gated ion channel causes what to happen to the receptor?
changes conformation, resulting in the opening of the channels
opening of ligand gated ion channel results in ___
action potential
the time from the ligand binding to the gated ion channel receptor to when there is a physiologic response (such as muscle contraction) is very __
fast
give an example of GPCR
beta adrenergic receptors
___ is the largest class of drug-targeted receptors
GPCR
it is estimated that approximately ___% of drugs interact with GPCR
50
A GPCR has __ transmembrane domains with an ___ formed within them
7; agonist binding site
the intracellular domain of a GPCR interacts with the __
G protein complex
when an agonist binds to the GPCR pocket, there is a conformational change in the large ___ protein, which facilitates now the exchange of ___ for ___
G; GDP for ATP
what happens to the high-energy G protein complex and the G protein subunits after exchanging GDP for GTP?
the high energy G protein complex dissociates from the receptor and the subunits (alpha and beta) separate and initiate intracellular signalling cascades
when epinephrine activates the beta-adrenergic receptors in the heart, what g-protein is activated?
G alpha s (stimulatory_
when a GPCR is coupled to a Gs protein, the activated __ subunit dissociates and increases the __ activity of ___
alpha; enzymatic; adenyl cyclase
adenyl cyclase catalyses the reaction that converts __ to __
ATP to cAMP
what is cAMP and its role?
second messenger within cells that activates other proteins
one of the primary effector molecules activated by the Gs signalling pathway is the ___. what are 4 cellular roles of this effector molecule?
protein kinase A; increase heart rate and calcium, increase metabolism, increase hormone production
___ is the mediator responsible for initiating the cellular changes that increase heart rate and contractility when epinephrine activates the beta-adrengeric receptors
protein kinase A
another common G alpha protein is ___
G alpha I / Gi (inhibitory protein)
G alpha I inhibits ____ and reduces the cellular production of __
adenyl cyclase; cAMP
G alpha I has an inhibitory effect in cells that regulates activities of __ and __
second messengers and mediators
provide an example of G alpha I receptors
M2 and M4 muscarinic receptors in the PNS
activation of Gs and Gi receptors converge on __ , the enzyme that produces __
adenyl cyclase; cAMP
when Gs and Gi are activated simultaneously, there will be ___ input into adenyl cyclase enzymes within a cell. why is this?
competing; because most cells in the body express many receptor types and it is possible that several are being modulated by endogenous molecules and drugs at the same time
the overall cellular response when there are many competing inputs will be ___
the net integration of all the inputs
t/f the observed physiologic response may be the result of many signalling pathways converging
true
what is a third type od G-alpha protein?
Gq
activated G alpha q enhances the activity of the cellular enzyme __
phospholipase c (PLC)
Gq enhancing the activity of PLC increases the production of ___ an d__ by splitting the membrane phospholipid __
IP3 and DAG; PIP 2
increased cellular levels of IP3 causes release of __ which promotes contraction of ___ and is also able to modulate other ___ and act as a ___
Ca2+; smooth muscle, proteins; second messanger
DAG can activate other ___ and ___ such as __ to cause further intracellular changes
enzymes and kinase; protein kinase C
give 2 examples of Gq coupled receptors
alpha 1 and the odd numbered muscarinic receptor
t/f there are many more subtypes of Gbeta and Ggamma than G alpha, which results in a lot of combinations of G. beta gamma
true
do the beta and gamma subunits remain together when the G protein dissociates from the receptor?
yes
the extent of G beta gamma downstream effects are not as well __as for G alpha
described
some key cellular effects of G beta gamma are the interactions and modulations of __ in __, which alters the __ of these cells
ion channels in neurons; excitability
in order to regulate cellular response and prevent over stimulation, the activation of G-protein receptors also initiates a __
regulatory cascade to terminate the signalling response
after the G protein dissociates, the receptor remains on the ____. Kinases called ____ phosphorylate the __ of the receptor, which prevents the association of another ___
cell surface, G-protein coupled receptor kinase (GRK); G-Protein
receptor desensitization typically occurs within __ of exposure
minutes
what is receptor desensitization?
cellular response to agonist declines (due to phosphorylation of receptors) even though the agonist is still present
in receptor desensitization, the response will not go completely to __ when the agonist is still present, but will be significantly reduced
baseline
___ binds to the phosphorylated tail of the inactivated complex, causing the receptor to be ___
beta-arrestin; internalized
once internalized, what are the two options for the fate of a receptor?
can be recycled and brought back to the surface of cell or can be broken down by lysosomes
if the cell decides to recycle a receptor, what 2 things have to be removed?
agonist and phosphate groups
the brief periods of agonist exposure with periods of none present promotes receptor ___ and ____ of the cell
recycling and desensitization
what is desensitization of receptors?
the receptors that have been recycled are moved back to the surface when no agonist is present, and will be ready to accept more if it comes
if the cell is being overstimulated, what is it likely to do with the internalized receptors?
break them down in lysosome
process of moving receptors to the cell surface is called __
receptor traficking
if the cell has fewer receptors available, even after a period of no agonist, when the agonist comes back, the response may be ___ this is a hallmark of __
smaller; receptor downregulation
when a cell chooses to break down its receptors, the full response cannot be achieved agin until___
new receptors are made
the majority of our considerations of the actions of drugs will be based on which step of the G-protein life cycle ?
the first, agents binding to receptor and initiation of response
___ exposure to agonist promotes quick turn around times between desensitization and resensitization, which promotes repeated physiologic responses
brief
___ exposure to agonist promotes ___ of receptor to prevent overstimulation
long; down regulation
t/f there are any druggable targets which are not receptors
true
cellular enzymes are important drug __
targets
give 2 examples of drugs that target enzymes and how they work
ACE inhibitors that reduce blood pressure by decrease enzyme production of angiotensin. 2) cyclooxyrgenase inhibitors have anti-inflammatory effects by reducing the synthesis of inflammatory mediators
give 2 examples of drugs that do not have a specific target but rather change the physiologic environment
antacids that act by simple acid-base chemistry to neutralize stomach and 2) osmotic laxatives attract water to be absorbed into the intestine to relive constipation
