Pharm 737 Exam 3 Flashcards
What are the 4 components of Receptor Theory of Drug Action?
A. Drugs do not Create effects
B. No drug has a single action
C. Intensity of response is typically proportional to concentration of free drug
D. Agents can not act unless bound
What is Cell Signaling?
Process by which cells release, transmit, receive and respond to information.
What are 5 types of Intercellular Signaling molecules/mechanisms?
A. Endocrine Signaling B. Paracrine Signaling C. Autocrine Signaling D. Juxtacrine Signaling E. Gap Junctions & Plasmodesmata
What is Endocrine Signaling used for?
“distant” signaling via the bloodstream, e.g. steroid hormones and insulin
What is Paracrine signaling used for?
Locally acting signals, e.g. Nitric Oxide, Histamine, Neurotransmitters
What is Autocrine signaling used for?
Self-activating signals, e.g. growth factors
What is Juxtacrine signaling? what is it used for?
Contact-dependent signaling, Cell-cell or cell-substrate signaling e.g. integrin signaling
What are Gap Junctions and plasmodesmata used for?
Direct cell to cell transfer e.g. 2nd messengers.
How is Signal Transduction accomplished? What are the required components?
Requires: Ligand, Receptor, Amplifier, 2nd messengers, Effector Enzymes, and signaling cascades.
What are some of the most common 2nd messengers and signal switches?
cAMP, cGMP, Calcium Ions, IP3, DAG
- Signaling by Phosphorylation (cAMP etc)
- Signaling by GTP-binding (IP3 etc)
- Signaling by Proteolysis (DAG etc)
What types of cell responses may you see from the same ligand?
A. Survival B. Division (proliferation) C. Differentiation D. Death (apoptosis) E. Contraction F. Secretion
What are the different Receptor Motifs and what/how is their respective transduction time?
Ligand-Gated Ion channel - fast/msec
Enzyme-linked receptor - medium/sec
G protein-coupled receptor - medium/sec
Steroid Hormone/Nuclear Receptor - slow/min-hr
What do Ion channels do?
How does an Ion flux work?
Ion Channels - regulate the flow of ions across membranes selective for specific ions
Ion Flux - Movement of ions across a membrane changes the voltage (electrical potential) and changes the intracellular concentrations of ions. this may directly stimulate signaling paths
What are the different types of ion channels?
Voltage-gated - transmembrane voltage changes will open/close the channel
Ligand/2nd messenger-gated - small molecule binds to and opens or closes the ion channel
What are the relative concentrations of ions in and outside the cell?
Na+ -> High out, Low in
K+ -> Low out, High in
Cl- -> High out, Low in
Ca++ -> High out, Low in
Which drug targets a Voltage-gated ion channel and how does it work?
Vasolidators such as Nifedipine will target voltage-gated ion channels by blocking calcium channels in blood vessels
What drugs target Ligand-gated ion channels and how do they work?
Benzodiazepines like Valium are anti-axiety/sedative drugs because they enhance the effects of GABA at the GABAa receptor ion channel.
How do Voltage Gated Ion channels create an Action Potential?
- Initial depolarization by some change in membrane potential.
- Depolarization occurs and opens voltage sensitive Na channels once threshold is reached. Na flows in and inc. Depolarization.
- Maximum depolarization occurs and Na channels close and K channels open. K then flows out of the cell to repolarize the cell.
- Hyperpolarization occurs, closing the K channels and brings a return to resting potential.
How are Ligand-gated ion channels activated/inactivated
Multiple subunits form a central pore
Agonist binding opens the pore to ion flow
A further conformational change inactivates the channel
The ion channel is “reset” to a closed state and ready to be activated
In fast neurotransmission occurring at neuromuscular junctions, how is neurotransmitter decidely taken or blocked?
Modulators, which can either inhibit or amplify the receptor binding affinity for NT ligand.
How do second-messenger regulated ion channels work?
Small molecule ligands that are located on the inside of cell. Things like ATP, cyclic nucleotides (cAMP) lipids, ions or other small molecular second messengers to convey signals.
How do cells respond to low glucose state? In this state, describe the cells polarization and the position of K and Ca channels
Low levels of glucose = low ATP, (cell is quiet)
The low ATP keeps Katp channel open so the cell is hyperpolarized
Ca++ channels stay closed, and insulin stays inside
How do cells respond to high glucose state? In this state, describe the cells polarization and the position of K and Ca channels
High glucoses stay = Inc ATP
ATP closes Katp channels
Cell is depolarized, Ca++ channels open and insulin is secreted.
What is the structure of G protein coupled-receptors? How do they interact with G protein?
7 transmembrane helices form a barrel and 3 intracellular loops and a carboxyl tail.
They interact with G proteins on the inside of the cell, which can signal effector enzymes and channels –> intracellular messengers
What are some types of drugs which act through GPCRs?
Marijuana (Cannabinoid receptors)
Antihistamines
Opiod Analgesics
within the Heterotrimeric G protein/GTPase cycle, How is GTPase activtyable to reset GDP from GTP?
GTPase hydrolyzes GTP back to GDP (RGS accelerates the GTPase activity)
The alpha beta and gamma go on to produce modulation effectors
What is cholera toxin’s effect on G alpha s (Gas), what is its major enzyme effector and 2nd messenger/effect?
Permanently activates cell
Adenyl Cylclase (Ca++ and Na+ channels)
increases cAMP, results in cell depolarization
What is Pertussis toxin’s effect on G alpha i (gai) do, What is its major enzyme effector and 2nd messengers/effect
Permanently inhibits cell
Adenyl Cyclase (Ca++ and Na+ channels, cGMP phosphodiesterase)
Decreases cAMP, cell hyperpolarization, and decreases cGMP)
How do Stimulatory hormones and Inhibitory hormones work in Adenylyl cyclase pathways?
Stimulatory go through Gas
Inhibitory go through Gai
Adenylyl cyclase uses ATP to creat cAMP, but if inhibited, available ATP increases over time from not being used.
How does Phospholipase C-B act as an effector in signaling?
It is activated by G proteins, then relays to release IP3 which opens CA++ channels on the lumen of endoplasmic reticulum
How does GPCR internalization reduce signaling?
Desensitization, GRK reduces the drug effects over time, (Eg drug tolerance progression of heart disease)
What is the purpose of 7 transmembrane receptors?
They are required in development for axis polarity, cell specification, proliferation and epithelial to mesenchymal transition.
Allows Non-G Protein-coupled signaling.
What is WnT/Fz signaling associated with?
Enhanced Wnt/Fz signal is associated with metastsis (EMT) in cancer.
What is the Hedgehog signaling pathway how does it function?
Hedgehog (Hg) ligand is required in embryonic development but abnormally active in certain cancers.
- Hh receptor is patched (PTCH) this normally keeps the smoothed (SMOH) transducer sequesterd and inactive.
- Hh binding to PTCH allows SMOH to travel to plasma membrane and interact with a cluster of proteins including GLI
- SMOH activates GLI to translocate to the nucleus and activate gene transcription
Guanylyl Cyclase (GC Receptors) are primarily responsible for?
Conversion of GTP to cGMP as a 2nd messenger.
They are single transmembrane domain receptors with intrinsic intracellular guanylyl cyclase activity.
Soluble GC’s are similar but without the extracellular domain.
What are the main functions of GC receptors?
Production of nitrates
Smooth muscle relaxation & vasodilation
Sildenafil for erectile dysfunction
What pathway is used to activate GF and what are some examples of activators?
Receptor Tyrosine Kinase (RTK) pathway
EGF - epidermal GF NGF - Nerve GF FGF - Fibroblast GF IGF - Insulin-like GF Ang - Angiopoietin VEGF - Vascular Endothelial GF PDGF - Platelet Derived GF BDNF - Brain-derived neurotrophic Factor
Describe the Physiology and Anatomy of Receptor Tyrosine Kinases
Single Transmembrane domain
Intrinsic intracellular tyrosine kinase activity
Phosphorylates self and cytoplasmic substrates to activate signaling paths through activation of adaptors
Scaffolds are important to the phosphorylation cascade.
What is the structuce of Small GTPases and what is their activity seen in?
Only an alpha-subunit
Activated by Intracellular GEF’s
Their Intrinsic GTPase activity is accelerated by GAPs
Overactive mutants in some cancers
How do RTK’s reduce signaling?
Internalization, similar to desensitization in GPCRs, E.g. Cancer drugs: TKIs block kinase activity for glioma, esophageal and renal cancers
How do Cytokine Receptors use their signaling pathway?
Transmit signals through an associated (not intrinsic) kinase, JAK.
What are the functions of Cytokines?
Mediate Immune responses and inflammation
Stimulate Hematopoiesis
Function in reproduction
What are some common ligands (and their function) for Integrin Receptors?
Fibrinogen - activate platelets to form thrombi
Invasin - (on bacteria) activates host cells to allow bacterial uptake
ICAM-1 - (endothelial cells) activate leukocytes to allow extravasation
What type of signaling is demonstrated by Death Domain Receptors
Joxtacrine signaling
How are DDRs similar to CRs and how does their signal transmission function/terminate?
Transmit signals through a proteolytic (cleavage) signaling cascade resulting in apoptosis of cell.
(mutations along this pathway can be responsible for some cancers that refuse to self-terminate)
What type of signaling is required for T cell development?
Delta/Notch
Mutations of this lead to constitutive nuclear localization of notch tail, causes human T cell Leukemia
What are characteristics of Nuclear Hormone Receptors?
Intracellular, soluble, non-membrane-associated proteins that function as ligand-dependent transcription factors
48 members of the family in humans
Play diverse role in regulation of growth, development and homeostasis
One of the best studied and understood classes of
transcriptional regulators
Function as Dimers
In Type 1 Nuclear Receptor Transcriptional regulation pathway, explain the role of Aldosterone and HSP-MR complex
Aldosterone crosses cell membrane and binds to Hsp-MR. this complex then separates HSP from the aldosterone homodimer, which breaks down proteasomes.
In Type II Nuclear receptor transcriptional regulation pathway, how does the P300 co-activator complex return to its original state?
After the complex finishes synthesis, the entirety of the complex is targeted for break down. some parts are exported as waste, while some are recycled in the cell.
What are some Steroid Hormone receptors and what drugs interact with that receptor?
Glucocorticoid - Prednisone (anti-inflammatory, immunosuppresion)
Progerstone Receptor - Mifepristone (Pregnancy Termination)
What are the 5 characteristics of Drug and Receptor Binding?
- Saturable
- Reversible
- High Affinity
- Stereoselective
- Causes an Effect
Define Saturable
Drugs must act through specific sites which are limited
Define Reversible
Receptors are not enzymes, drugs are unchanged by binding receptors
Define High Affinity
Specific actions require high affinity interactions
Define Stereoselective
Consequence of high affinity interactions
What effect should drug and receptor binding produce?
Activation of a signaling pathway
