Describe the pathway of the serine/threonine kinase receptor
- TGF-B binds to the extracellular region of the type II receptor causing it to dimerize with the type I recepter.
- The type II receptor phosphorylates and activates the type 1 receptor
- The activate type I receptor binds and phosphorylates SMAD
- Phosphorylated SMAD leaves the receptor and binds coSMAD and translocates to the nucleus
- This results in the inhibition of epithelial growth
Describe the pathway of Janus Kinase receptors
- Cytokines (INFy, IL) bind to a receptor which is continuosly bound to JAK
- The receptor dimerizes with another receptor and the JAKs phosphorylate each other.
- The Phosphorylated JAKs phosphorylate a tyrosine on the receptor creating an SH domain.
- STAT binds and is phosphorylated
- Phosphorylated STAT dimerizes and heads to the nucleas to activate transcription
What is a major disease that occurs when the JAK/STAT pathway is blocked?
Severe Combined Immunodeficiency Disease results becasuse the JAK/STAT pathway of the cytokines is critical for the differentiation of the agranulocytic leukocytes lineages
Describe the action of tyrosine kinase receptors for EGF
- EGF binds causing the receptor to homodimerize
- Receptors phosphorylate tyrosine residues on each other creating SH domains
- GRB2 binds which causes SOS to exhange GDP for GTP on RAS
- Activated RAS binds RAF (MAPKKK)
- MAPKKK phosphorylates to MAPKK and MAPKK phosphorylates to MAPK which activates transcription factors and turns on genes
What happens when there is excess HER2 present in the membrane?
HER2 dimerizes with the receptor for EGF and starts the RAS/RAF pathway leading to cellular proliferation and cancer (this is the cause of 30% of breast cancer)
Herceptin can block HER2 helping to keep this from happening
Describe the insulin receptor pathways
- Insulin receptor has 2 subunits, the intracellular subunits phosphorylate one another when insulin binds
- The phosphorylate B subunit binds IRS which it phosphorylates on a tyrosine to form an SH domain
- IRS can bind GRB2 (RAS/RAF), PLCy (DAG/IP3), or PI3 kinase which adds a phosphate to PIP2 to form PIP3
- PIP3 binds PDK1 and ACT which phosphorylates akt causing the number of glucose transporters to rise on the membrane
Describe the mechanism of action of GPCRs
- Ligand binds to receptor causing it to phosphorylate GDP attached to Ga subunit into GTP
- The Ga subunit dissociates from the receptor and from Gb and Gy subunits and binds to Adenelyl cyclase
- AC causes the production of more cAMP which activates PKA and causes glucose production in the muscle and liver (when glucagon binds)
What happens when cholera is present?
Cholera prevents the Ga subunit from automatically hydrolyzing bound GTP to GDP. This results in overproduction of cAMP and overstimulaton of the CFTR which causes Chloride to leak into the lumen. This binds with NaH to form salt causing the cells to secrete water into the lumen resulting in diarrhea.
Pertussis does what?
Pertussis prevents the Gai subunit from binding to adenylyl cylclase in the lungs resulting in the overexpression of cAMP. It is not well understood how this contributes to disease.
What is special about the Gaq subunit?
- It turns on phospholipase C resulting in the conversion of PI2 to DAG and IP3. This causes the release of calcium into the cell and also the phosphorylation of a number of proteins increasing cellular activity.
To what kind of receptor does Acetylcholine bind?
To what kind of receptor does Angiotensin II bind? What inhibitor prevents this?
GPCR, ACE inhibitors block the conversion of Angiotensin I to Angiotensin II
What is the equation for the relative risk? Is it for cohort or case control studies?
Relative Risk Ratio = (A/A+B)/(C/C+D), it is used in cohort studies (it is the incidence)
What is the equation for Prevalence Ratio, what kind of studies is it used in?
PR = (A/A+B)/(C/C+D), Cross sectional studies
If the relative risk is less than 1 what is it called?
The protective effect
What is the equation for attributable risk?
AR = Iexp - Iunexp, this is used in cohort studies to determine the risk that is associated with the behavior
What is the equation for population attributable risk?
PAR = Prevalence of Exposure x AR, it is used to determine the number of diseased cases that are caused in a population by the risk factor
What is the formula for an odds ratio? What is it used for?
It is used for case control studies, OR = (A/C)/(B/D) = AD/BC
What does an OR greater than 1 indicate?
What is secreted by normal endothelium to inhibit formation of thrombosis?
- TPA breaks down fibrin
- NO, PGI2 and ADP prevent platelet aggregation and promote vasodilation
- Tissue Factor Pathway Inhibitor inhibits the extrinsic pathway preventing clot formation
- Heparin-like molecule binds antithrombin III to prevent activity of thrombin
- Thrombomodulin binds thrombin and stimulates protein C and protein S which inhibit Factor V and factor VIII
What is sensitivity of a test?
How many does it catch that have the disease? TP/TP+FN
What is specificity?
What is false negative rate?
What is false positive rate?
When do you want a specific test?
When a false negative is worse than a false positive