Week 2 (Quiz 2) Flashcards
Ligand
substance that binds a receptor (often reversible)
Receptor
protein that interacts with a ligand to initiate a physiologic response.
______ allows for signal amplification, coordination of multiple processes from single stimulus and precise regulation of cellular events.
Signal transduction cascade.
Emax
maximum efficacy of a drug, all receptors are bound.
E1/2
half of the maximum response, used to find the ED50
ED50
effective dose or effective concentration eliciting
half of the maximum response; a measure of drug potency
More potent drug has a ___ ED50
lower (less drug is
needed to elicit half of the maximum response)
Threshold dose
dose at which the drug starts eliciting a response
Maximal Effective Dose
dose required for a maximal response
Therapeutic Index equation
LD50/ED50
LD50 (lethal dose)
Concentration at which 50% of subjects will die
Higher therapeutic index means
the ED50 and LD50 are
farther apart = “safer” drug
PCN has a high or low TI
high!
Coumadin, Digoxin, Chemo have a high or low TI
low! — more dangerous
Therapeutic Window
concentration range that elicits response
w/o unwanted side effects
Agonists
elicit response from receptor
Full agonist
elicits max response (curves 1 and 2 on graphs)
Partial agonist
elicits partial response, will never reach max
Antagonists
bind receptor but don’t induce response
Competitive antagonists bind:
Ligand-binding site
Competitive antagonists _____ ED50
Increase
Competitive antagonists shift curve _____
right
Competitive antagonists _____ Emax
Do not alter
Competitive antagonists (potency and efficacy)
decreases potency, efficacy remains the same.
Non-competitive antagonists bind:
receptor away from ligand-binding site
NC antagonists ____ Emax
decreases
Drug dose and NC antagonists
Cannot be overcome by increasing dose
Spare receptors
when drug achieves max response without using all available receptors
Desensitization
repeated/continuous dose that alters (usually decreases) responsiveness of receptor to drug
Ligand-gated ion channels
Ligand-binding causes channel to open; Fastest acting (milliseconds)
2 examples of ligand-gated ion channels
Nicotinic receptor (Ach) – allows sodium to enter cell -> depolarizes
GABA (y-aminobutyric acid) – allows chlorine to enter cell -> hyperpolarizes
G-protein coupled receptors
Largest family of proteins in body; largest receptor and therapeutic target class; response in seconds
Ligand binds –> inactive (GDP bound) G-protein loses GDP and binds GTP –> α-GTP (active) dissociates from βγ
and receptor
Structure of G-protein coupled receptors
7 TM domains, heterotrimeric G-protein (3 domains aby)
The alpha subunits of the GPCR are
the main effector, bind GTP
Gs
promotes adenylyl cyclase –> ATP to cAMP –> activates PKA –> phosphorylates proteins like
RyR2 –> increase intracellular calcium (muscle contraction)
Types of Gs subunits
“Big Boys Don’t Have Vaginas” β-adrenergic1,
β-adrenergic2, Dopamine1, Histamine2, Vasopressin2
Gi
inhibits adenylyl cyclase –> no activation of PKA
Gi receptor types
“MAD 2s” - Muscarinic2, α-adrenergic2, Dopamine2, (Muscarinic4) [also
Histamine3 and Histamine4]
What is the M2 receptor responsible for?
for shaving-induce bradycardia via activation of βγ subunit activating potassium channels (see next page for ions and action potential)
Gq
activates phospholipase C –> cleaves PIP2 into DAG and IP3 –> DAG activates PKC and arachidonic
acid; IP3 increases intracellular calcium
Gq receptor types
“Gq HAVE 1 M&M” - Histamine1, α-adrenergic1, Vasopressin1,
Muscarinic1, Muscarinic3, (Muscarinic5)
By subunit
ion channel regulation i.e. potassium channels
Kinase-linked receptors
Heterogeneous group that signals through enzymatic cascade (hours)
Kinase-linked receptors structure
Single helical TM domain connecting receptor and kinase domains
Kinase-linked receptors mechanism
bind ligand –> receptors dimerize –> auto-phosphorylation –> phosphorylation binding protein (PbP) binds
kinase domains and initiates signal
Growth Factor (EGF) (Kinase-linked receptor)
Grb2 (SH2 domain) binds kinase and is phosphorylated –> Ras –> Raf –> Mek –> Erk –> to
nucleus to phosphorylate transcription factors which turn genes on
Cytokine (IL1) (Kinase-linked receptor)
Jak binds kinase domain, Stat binds kinase domain, is phosphorylated –> Stat dimerizes, moves to
nucleus and activates transcription
Nuclear receptors
non-membrane proteins (in cytosol or nucleus) that interact directly with DNA upon ligand binding (no
transduction cascade); take hours
2 Examples of Nuclear Receptors
Thyroid hormone receptor
and estrogen receptor
Estrogen receptor and Tamoxifen
Tamoxifen (drug for breast cancer) binds ERα and competes with estrogen which normally
creates complex that activates genes that promote breast cancer cell growth and division
Main cation inside the cell
Potassium; will efflux when channels are open (repolarize)
Main cation outside of cell
Sodium; will influx when channels are open (depolarize)
Divalent cation outside of cell
Calcium; will influx when channels are open
Anion outside of the cell
Chloride
Eca
+150 mV
Ena
+70 mV
Ek
-98 mV
Nerst equation
Es = 27ln ([S] outside)/([S] inside)
Time 0 in the action potential
Rapid depolarization: rapid sodium
channels open in response to stimulus (i.e.
nicotinic receptor); membrane depolarizes
to about +47 mV
What happens if the cell resting potential is higher than -96 mV?
if cell resting potential is higher
than -96mV the cell is less excitable,
because some fast channels will be
inactivated
Time 1 in the action potential
Inactivation of fast sodium channels; transient outward potassium channels open (chlorine also goes out); small downward deflection of membrane potential
Time 2 in the action potential
Plateau phase: L-type calcium channels
open, balancing out the flow through slow
delayed rectifier potassium channels
Time 3 in the action potential
Rapid Repolarization: L-type calcium channels close; Slow delayed rectifier potassium channels remain open; voltage sensitive rapid delayed rectifier potassium channels and inwardly rectifying potassium current are open
Time 4 in the action potential
resting membrane potential: KI (inward
rectifying current); potassium channels
keep membrane repolarize
Effects of activating potassium channels
increases repolarization, prevents contraction (i.e. vasodilation, shaving induced bradycardia)
Effects of inactivating potassium channels
decreases repolarization, prolongs action potential
Effects of activating calcum or sodium channels
promotes depolarization
What is torsades de pointes?
French for “twisting of the points”; rare variety of ventricular tachycardia where the ECG demonstrates polymorphic ventricular
tachycardia and the illusion that the QRS complex is twisting around isoelectric baseline.
What can tosades de pointes cause?
Can cause drop in BP, seizures, and syncope and degenerate into VF –> sudden cardiac death
What is long QT syndrome?
delayed repolarization of heart following a heartbeat - increased risk of
torsades (involves a K+ channels) –> causes differences in refractory period of
myocytes –> arrhythmias
What can cause early after-depolarizations?
L-type calcium channels (open during plateau phase)
When are people with long QT syndrome at increase risk for death?
adrenergic states (stress or excitement)
Long CT syndrome can be ____ or ____
genetic or drug induced
Drug induced long QT syndrome
Drug binds (to inner mouth) and inactivates HERG ion channel responsible for Ikr (K rapid delayed rectifying current responsible for rapid repolarization of membrane)
Genetic long QT syndrome
Various polymorphisms that a pt can have, corresponding to a different type of LQTS (LQT1, LQT2. . ., etc.)
About 10% people have a mutation –> genetically predisposed to LQTS
Which population have SCN5A Y1102 polymorphism?
African American
