L23 - calcium signalling 2

Question 1

structure of the endothelium

Answer 1

single layer lining of the innermost walls of blood vessels

consist of luminal (exposed to blood) and abluminal side (connections to VSMCs)

Question 2

what is a myoendothelial projection

Answer 2

Tiny membranous projections that extend from ECs through the internal elastic lamina towards VSMCs

Question 3

Acetylcholine-induced vasodilatation is dependant on which two factors

Answer 3

presence of functional endothelium
endothelial nitric oxide synthase activation

Question 4

activation of Ca+ dependant eNOS activation

Answer 4

1. ligand (Ach) binds at receptor
2. activation of Gaq
3. activation of PLC
4. conversion of PIP2 to IP3 + DAG
5. IP3 receptors on ER activate
6. Intracellular Ca+ is released
7. activation of eNOS
8. eNOS conversion of L-arg to NO
9. NO diffuses into VSMC
10. activates cGMP
11. RELAXATION

Question 5

what role do calmodulins play in eNOS activation

Answer 5

Calmodulins bind with calcium to promote eNOS phosphorylation/ activation at Ser1177

Question 6

two major function of Ca+/calmodulin activation of eNOS

Answer 6

1. this binds to eNOS releasing it from caveolin-1 (at the PM) placing it in active confirmation
2. Supports electron flow required for
   converting L-arginine into nitric oxide

Question 7

what mediates relaxation in smaller diameter arteries

Answer 7

mediated by endothelium derived hyperpolarization e.g. mesenteric
arteries or cerebral arteries

Question 8

how is small muscle relaxation mediated

Answer 8

1. intracellular cell concentration of ca+ increases via TRPs
2. ca+ binds to IK/SK
3. IK/SK channels open effluxing K+
4. membrane hyperpolarisation
5. hyperpolarisation spreads to adjacent VSMC ↓ L-type channel opening

Question 9

TRUE or FALSE: IK (intermediate conductance) and SK (small conductance) channels are voltage gated

Answer 9

FALSE - they are ca+ ligand gated (300-700nm of Ca+)

Question 10

4 Connexins of MEPs

Answer 10

Cx37, Cx40, Cx43, Cx45

Question 11

TRUE or FALSE: MEPs gave a proportional relationship to vessel size

Answer 11

FALSE: MEPs have an inverse relationship - larger vessel shave less and smaller vessels have more

Question 12

control of VSM via MEPS

Answer 12

Contraction
1. Phey binds to a1 receptor on VSMC releasing DAG + IP3
2. DAG opens L-type ca+ channels influxing ca+
3. vasoconstriction
Relaxation
1. IP3 and Ca+ move to EC via MEPs
2. IP3 binds to IP3R on ER → release Ca2+store
2. IP3 opens TRPV4 channel → Ca2+ influx
3. major influx of Ca+ causes IK/SK opening –> hyperpolarisation

Question 13

what is flow induced vasodilation

Answer 13

sheer stress caused by forceful blood flow activates a variety of channels on endothelial cells

Question 14

what channels are activated by sheer stress

Answer 14

P2X, PIEZO1(main), TRPP1, TRPV4

Question 15

how is vasodilation mediated by sheer stress

Answer 15

via the opening of channels on the endothelial cells an influx of ca2+ activates eNOS or IK/SK pathways

Question 16

how is hypertension caused by enhanced VSMCs excitability

Answer 16

overactive or upregulated voltage gets calcium channels causes excessive influx of calcium causing increased contraction

Question 17

how is hypertension caused by impaired endothelial function

Answer 17

an impaired endothelial cell function decreases the amount of eNOS released or IK/SK activated causing decreased vasodilatory signals

Question 18

how is hypertension caused by altered calcium-handling proteins

Answer 18

Inhibition of SERCA ca+ pumps reduces ca+ uptake in VSMC leading to prolonged intracellular ca+ elevation (prolonged vasoconstriction) and suppressed vasodilation