AL 17.2: Cell signaling Cases: cAMP

Question 1

List some examples of primary vasodialators

Answer 1

1) Bradykinin
2) shear stress from blood flow
3) prostaglandins
4) leukotrienes

Question 2

What is the mechanism of NO-mediated vasodialation

Answer 2

1) 1st messenger causes a release of Ca2+ (in endothelial cell) which activates NOS
2) NOS makes NO from L-Arg (citrulline byproduct)
3) NO diffuses into smc
4) NO then activates gaunylate cyclase
5) GC converts GTP into cGMP
6) increased cGMP decrease intracellular Ca2+
7) increased cGMP activates K+ channels leading to hyperpolarization
8) increased cGMP stimulates PKG that activates myosin light chain phosphatase (opposite of MLCK)

Question 3

What is the pathogenesis for Idiopathic Pulmonary Hyperternsion

Answer 3

1) narrowing of pulmonary arteries
2) smc proleferation, hypertrophy
3) we see a LOSS of NO

Question 4

What are some treatments of Idiopathic Pulmonary HTN

Answer 4

1) PGI2 (prostaglandins) analogoues
2) PDE-5i (decreases cGMP conversion to GTP)
3) Ca2+ channel blockers

Question 5

What is the pathogenesis of asthma?

Answer 5

1) inflammed airways, vasoconstriction, smc proliferation

2) we see EXCESS production of NO

Question 6

What are some txt for asthma?

Answer 6

1) PGI2 analogous
2) PDE-5i
3) corticosteriods/beta-2 agonists

Question 7

In asthma, why does excess NO lose its ability to vasodilate?

Answer 7

1) hyperactive airways
2) excess NO
3) ROS and RNS species so sGC stays in oxidized state
4) oxidized sGC cannot bind NO and NO can form more damaging RNS
5) desensitized sGC leads to lowered production of cGMP

Question 8

what is the function of PDE5 in smc

Answer 8

it catalyzes conversion of cGMP to GTP

Question 9

What are some positive regulators of NOS

Answer 9

1) Ach
2) Bradykinin
3) Serotonin
4) all of these increase intracellular Ca2+ in endothelial cells thus activating NOS

Question 10

what are some positive regulators of sGC

Answer 10

BAY proteins

Question 11

what are positive regulators of cGMP

Answer 11

PDE5i

Question 12

What are negative regulators of cGMP

Answer 12

PDE5

Question 13

What are the negative regulators of NOS, NO, and sGC

Answer 13

1) oxidative stress
2) aging
3) injury
4) endothelial dysfunction

Question 14

Explain vasodilation via GPCR

Answer 14

1) the agonist of the GPCR must cause DIRECT vasodilation
2) thus GPCR is DIRECT stimulation of smc (in lungs)
3) alpha subunit of of trimeric G-protein receptor is activated when ligand binds to 7-TM protein
4) activates adenylyl cyclase (ATP–> cAMP)
5) cAMP activates PKA which activates MLCP
6) cAMP also activates EPAC