Week 2 (Quiz 2) Flashcards
1
Q
Ligand
A
substance that binds a receptor (often reversible)
2
Q
Receptor
A
protein that interacts with a ligand to initiate a physiologic response.
3
Q
______ allows for signal amplification, coordination of multiple processes from single stimulus and precise regulation of cellular events.
A
Signal transduction cascade.
4
Q
Emax
A
maximum efficacy of a drug, all receptors are bound.
5
Q
E1/2
A
half of the maximum response, used to find the ED50
6
Q
ED50
A
effective dose or effective concentration eliciting
half of the maximum response; a measure of drug potency
7
Q
More potent drug has a ___ ED50
A
lower (less drug is
needed to elicit half of the maximum response)
8
Q
Threshold dose
A
dose at which the drug starts eliciting a response
9
Q
Maximal Effective Dose
A
dose required for a maximal response
10
Q
Therapeutic Index equation
A
LD50/ED50
11
Q
LD50 (lethal dose)
A
Concentration at which 50% of subjects will die
12
Q
Higher therapeutic index means
A
the ED50 and LD50 are
farther apart = “safer” drug
13
Q
PCN has a high or low TI
A
high!
14
Q
Coumadin, Digoxin, Chemo have a high or low TI
A
low! — more dangerous
15
Q
Therapeutic Window
A
concentration range that elicits response
w/o unwanted side effects
16
Q
Agonists
A
elicit response from receptor
17
Q
Full agonist
A
elicits max response (curves 1 and 2 on graphs)
18
Q
Partial agonist
A
elicits partial response, will never reach max
19
Q
Antagonists
A
bind receptor but don’t induce response
20
Q
Competitive antagonists bind:
A
Ligand-binding site
21
Q
Competitive antagonists _____ ED50
A
Increase
22
Q
Competitive antagonists shift curve _____
A
right
23
Q
Competitive antagonists _____ Emax
A
Do not alter
24
Q
Competitive antagonists (potency and efficacy)
A
decreases potency, efficacy remains the same.
25
Non-competitive antagonists bind:
receptor away from ligand-binding site
26
NC antagonists ____ Emax
decreases
27
Drug dose and NC antagonists
Cannot be overcome by increasing dose
28
Spare receptors
when drug achieves max response without using all available receptors
29
Desensitization
repeated/continuous dose that alters (usually decreases) responsiveness of receptor to drug
30
Ligand-gated ion channels
Ligand-binding causes channel to open; Fastest acting (milliseconds)
31
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
32
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
33
Structure of G-protein coupled receptors
7 TM domains, heterotrimeric G-protein (3 domains aby)
34
The alpha subunits of the GPCR are
the main effector, bind GTP
35
Gs
promotes adenylyl cyclase --> ATP to cAMP --> activates PKA --> phosphorylates proteins like
RyR2 --> increase intracellular calcium (muscle contraction)
36
Types of Gs subunits
"Big Boys Don't Have Vaginas" β-adrenergic1,
| β-adrenergic2, Dopamine1, Histamine2, Vasopressin2
37
Gi
inhibits adenylyl cyclase --> no activation of PKA
38
Gi receptor types
"MAD 2s" - Muscarinic2, α-adrenergic2, Dopamine2, (Muscarinic4) [also
Histamine3 and Histamine4]
39
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)
```
40
Gq
activates phospholipase C --> cleaves PIP2 into DAG and IP3 --> DAG activates PKC and arachidonic
acid; IP3 increases intracellular calcium
41
Gq receptor types
"Gq HAVE 1 M&M" - Histamine1, α-adrenergic1, Vasopressin1,
Muscarinic1, Muscarinic3, (Muscarinic5)
42
By subunit
ion channel regulation i.e. potassium channels
43
Kinase-linked receptors
Heterogeneous group that signals through enzymatic cascade (hours)
44
Kinase-linked receptors structure
Single helical TM domain connecting receptor and kinase domains
45
Kinase-linked receptors mechanism
bind ligand --> receptors dimerize --> auto-phosphorylation --> phosphorylation binding protein (PbP) binds
kinase domains and initiates signal
46
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
47
Cytokine (IL1) (Kinase-linked receptor)
Jak binds kinase domain, Stat binds kinase domain, is phosphorylated --> Stat dimerizes, moves to
nucleus and activates transcription
48
Nuclear receptors
non-membrane proteins (in cytosol or nucleus) that interact directly with DNA upon ligand binding (no
transduction cascade); take hours
49
2 Examples of Nuclear Receptors
Thyroid hormone receptor
| and estrogen receptor
50
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
51
Main cation inside the cell
Potassium; will efflux when channels are open (repolarize)
52
Main cation outside of cell
Sodium; will influx when channels are open (depolarize)
53
Divalent cation outside of cell
Calcium; will influx when channels are open
54
Anion outside of the cell
Chloride
55
Eca
+150 mV
56
Ena
+70 mV
57
Ek
-98 mV
58
Nerst equation
Es = 27ln ([S] outside)/([S] inside)
59
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
60
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
61
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
```
62
Time 2 in the action potential
Plateau phase: L-type calcium channels
open, balancing out the flow through slow
delayed rectifier potassium channels
63
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
```
64
Time 4 in the action potential
resting membrane potential: KI (inward
rectifying current); potassium channels
keep membrane repolarize
65
Effects of activating potassium channels
increases repolarization, prevents contraction (i.e. vasodilation, shaving induced bradycardia)
66
Effects of inactivating potassium channels
decreases repolarization, prolongs action potential
67
Effects of activating calcum or sodium channels
promotes depolarization
68
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.
69
What can tosades de pointes cause?
Can cause drop in BP, seizures, and syncope and degenerate into VF --> sudden cardiac death
70
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
71
What can cause early after-depolarizations?
L-type calcium channels (open during plateau phase)
72
When are people with long QT syndrome at increase risk for death?
adrenergic states (stress or excitement)
73
Long CT syndrome can be ____ or ____
genetic or drug induced
74
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)
```
75
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
76
Which population have SCN5A Y1102 polymorphism?
African American
