Signal Transduction and Receptor Regulation Flashcards
Describe G protein-mediated amplification
The receptor is embedded in the lipid bilayer and spans the membrane 7 times. An agonist binds to the receptor and a GPD is replaced by GTP. The G protein is intracellular space. The activated G protein can change the activity of effector proteins (ion channels)
Describe the calcium-phosphoinositide signalling pathway
The activated G protein stimulates the PLC (phospholipase C), which activates/stimulates enzymatic reaction that breaks down PIP2. PIP2 is broken into DAG and IP3. IP3 interacts with with calcium which is in a vesicle, releasing the calcium. DAG interacts and activates PKC, the central molecule in many biochemical reactions. PKC allows the conversion and contributes the biological response. Calcium is released and interacts with calmodulin (CaM). Calcium activates downstream processes
Explain desensitization/resensitization of receptors
Repeated administration of an agonist (such as epinephrine) over a short period of time results in diminished response. Following a period of rest, administration of the drug results in a response of the original magnitude
What is tachyphylaxis?
Tissue response to agonist wanes over time
Describe a common mechanism of desensitization/resensitization
Agonist binding to receptors initiates signalling by promoting receptor interaction with G proteins located in the cytoplasm. Agonist-activated receptors are phosphorylated by a G protein-coupled receptor kinase (GRK), preventing receptor interaction with G and promoting binding of a different protein, beta-arrestin to the receptor. The receptor-arrestin complex binds to the coated pits, promoting receptor internalization. Dissociation of the agonist from the internalized receptors reduces beta-arrestin binding affinity, allowing dephosphorylation of the receptors by a phosphatase and return of the receptors to the plasma membrane. Together, these event result in the efficient resensitization of cellular responsiveness. Repeated or prolonged exposure of cells to agonist favours the delivery of internalized receptors to lysosomes, promoting receptor down-regulation rather than resensitization
What are different ways drugs can cross membranes?
Passive diffusion through aqueous channels (driven by concentration gradients) Lipid diffusion (dependant on lipid solubility and pH) Transport by special carriers Endocytosis and exocytosis
What is Fick’s Law?
Flux (molecules per unit time) = (C1 - C2)*(area x permeability coefficient)/thickness
C1 = the lower concentration
C2 = the higher concentration
Area = cross-sectional area of the diffusion path
Permeability coefficient = a measure of the mobility of the drug in a medium
Thickness = length of the diffusion path
How can the therapeutic vs the toxic drug effects vary?
A drug and a receptor can affect an effector causing a toxic or beneficial effect
A drug and a receptor can affect one receptor causing a toxic effect, or another receptor causing a beneficial effect
A drug can interact with one receptor, affecting an effector, causing a toxic effect or it can interact with another receptor, affecting another effector causing a beneficial effect
What is the ED?
The effective dose
What is the LD?
The lethal dose
What is the TD?
The toxic dose
What is the clinical therapeutic index (Ti)?
The therapeutic index is the TD50 divided by the ED50
What is the importance of quantal responses?
We can use the data to plot the therapeutic window
What does a high Ti indicate?
The drug is safer than drugs with a lower Ti
Can we use drugs with a low Ti?
Yes, we do it all the time for cancer patients (chemotherapy). You have to weight the risks and the benefits
