Lecture 19. Intracellular Receptors

Question 1

How do intracellular receptors that are enzymes function?

Answer 1

An extracellular ligand diffuses across the plasma membrane and binds and activates its receptor
The activated receptor converts its substrate into product
The activity of downstream targets is altered

Question 2

How does nitrous oxide signal?

Answer 2

The gas nitric oxide (NO*) diffuses across the plasma membrane and binds and activates its receptor
The activated receptor (GC) converts GTP into cGMP
cGMPI is a second messenger that alters the activity of target proteins

Question 3

What is the main treatment for relieving angina?

Answer 3

Glycerol trinitrate (nitroglycerine)

Question 4

When do blood vessels dilate?

Answer 4

In response to high blood pressure

Question 5

What does blood dilation do?

Answer 5

Dilation increases the volume of the vessel and lowers blood pressure

Question 6

What stimulates NO* production in vivo?

Answer 6

High blood pressure

Question 7

How is NO* production stimulated in vivo?

Answer 7

1. Autonomous nerves in the vessel wall respond to high blood pressure (high shear force) and release acetylcholine (Ach)
2. Acetylcholine binds its receptors (AchR) on the plasma membrane of endothelial cells
   Stimulation by acetylcholine increases endothelial cell cytosolic [Ca⁺⁺]

Question 8

What signalling pathways is NO* involved in?

Answer 8

Control of capillary dilation
Control of blood vessel dilation
Control of peristaltic movement through the gut
Regulation of glomerular capillary pressure
Regulation of blood flow in the adrenal glands
Neurons of the corpus cavernosum (the erectile tissue in a penis): regulation of muscle contraction and blood flow

Question 9

Are all responses carried out via cGMP-dependent protein kinase?

Answer 9

There are cGMP-gated ion channels
There are cGMP-dependent phosphodiesterases

Question 10

What is NOS1/nNOS?

Answer 10

Neuronal isoform
Development of the nervous system, protection against cardiac arrhythmia induced by myocardial infarction (‘heart attack’), peristalsis and sexual arousal

Question 11

What is NOS2/iNOS?

Answer 11

Inducible isoform
Produces large amounts of NO* as a defence mechanism used by macrophages (chemical warfare)
It is also the cause of septic shock

Question 12

What is NOS3/eNOS?

Answer 12

Endothelial isoform
Controls vascular tone, insulin secretion, and regulates angiogenesis (growth of new blood vessels)
Plays a critical role in embryonic heart development and morphogenesis of coronary arteries and cardiac valves

Question 13

What is bacterial NOS/bNOS?

Answer 13

NO produced by bacterial NOS protects against oxidative damage, immune attack

Question 14

What is amyl nitrate?

Answer 14

Inhalation spray is commonly prescribed for a ‘weak’ heart
Amyl nitrite is a rapidly acting vasodilator (within 15 seconds)
It vaporises to generate NO*
The NO* dilates vascular smooth muscle
This results in coronary vasodilation and decreased systemic vascular resistance (lowered blood pressure)

Question 15

What are cyclic nucleotides?

Answer 15

Important secondary messengers that control many physiologic processes, including smooth muscle contractility

Question 16

What are phosphodiestserases (PDEs)?

Answer 16

A superfamily of metallophosphydrolases that specifically cleave the 3’,5’- cyclic phosphate moiety of cAMP and/or cGMP to produce the corresponding 5’ nucleotide

Question 17

What is Sidenafil citrate also known as?

Answer 17

Viagra

Question 18

What are oestrogens?

Answer 18

Primary female sex hormones

Question 19

What is E1 oestrogen?

Answer 19

Oestrone/estrone: predominant in the menopause

Question 20

What is E2 oestrogen?

Answer 20

Oestradiol/estradiol: predominant during the reproductive years

Question 21

What is E3 oestrogen?

Answer 21

Oestril/estriol: predominant in pregnancy

Question 22

What is E4 oestrogen?

Answer 22

Oestetrol/estretol: also produced during pregnancy

Question 23

What is the structure of oestrogen receptors (ER)?

Answer 23

The ER has an N-terminal transactivation domain, a DNA-binding domain, and a hormone-binding domain that can bind oestrogens
It is stored in the cytosol in complex with a dimeric chaperone protein called Hsp90
Hsp90 binds near the ligand-binding site and maintains the ER in a soluble state
The Hsp90: ER complex is too large to enter the nucleus

Question 24

Why is steroid hormone signalling unusual?

Answer 24

No amplification

Question 25

What are the two different forms of the ER named and what are they encoded by?

Answer 25

ERα and ERβ encoded by separate genes ESR1 and ESR2, respectively)

Question 26

What is used to treat both early and advanced ER+ (oestrogen receptor positive) breast cancer females?

Answer 26

Tamoxifen

Question 27

What is tamoxifen?

Answer 27

Tamoxifen is a non-steroidal ER antagonist that is larger than estradiol and so the loops cannot take on their active conformation. Oestrogen signalling via ERs is inhibited. Tamoxifen also causes cells to remain in the G₀ and G₁ phases of the cell cycle