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Cell and Molecular > L20 - Signalling Via Intracellular Receptors > Flashcards

L20 - Signalling Via Intracellular Receptors Flashcards

1
Q

Why are some signalling molecules intracellular?

A

Some signal molecules are hydrophobic or small enough to pass across the plasma membrane and interact directly with intracellular enzymes or receptors

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2
Q

What are two examples of signalling via intracellular receptors?

A

Nitric oxide

Lipid soluble signalling molecules e.g. retinoic acid

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3
Q

Receptors bound by lipid soluble signalling molecules are?

A

Structurally related and form the nuclear receptor superfamily

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4
Q

What are the two types of receptors involved in signalling via intracellular receptors?

A

Intracellular receptors

Nuclear receptors

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5
Q

What are intracellular receptors?

A 
Nitric oxide (NO•)
Carbon monoxide (CO)
Often have carrier proteins associated with them
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6
Q

What are nuclear receptors?

A

Steroid hormones
Thyroid hormones
Retinoids
Vitamin D

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7
Q

What are the 3 key properties of nitric oxide?

A

Gaseous
Free radical - unpaired electron in outer shell
Very reactive - half-life 5-10s

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8
Q

What are the 3 side molecules produced in the two successive oxidations to produce nitric oxide?

A

L-arginine –> N-hydroxyarginine –> L-citrulline + NO

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9
Q

What enzyme catalyses the oxidations to produce nitric oxide?

A

Nitric oxide synthase (NOS)

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10
Q

What sort of expression does constitutive NOS have?

A

Expression constitutive – expressed all the time

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11
Q

What is constitutive NOS induced by?

A

Enzymatic activity induced by Ca2+/calmodulin
When Ca activates them the activity is short-lived
- Produces picomoles of NO

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12
Q

When activated what does constitutive NOS form?

A

Picomoles of NO

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13
Q

What are the two types of constitutive NOS?

A

eNOS – endothelial

nNOS – neural

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14
Q

Where is eNOS expressed?

A 
Bound at cell membrane 
Endothelium 			
Cardiac myocytes			
Renal mesangial cells		
Osteoblasts/osteoclasts
Platelets
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15
Q

Where is nNOS expressed?

A 
Found in the cytoplasm
CNS
NANC neurons
ENS
Retina
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16
Q

What is induced NOS induced by?

A

Transcriptionally induced in response to pathological stimuli - LPS, IFN-g, IL-1

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17
Q

What kind of activity does inducible NOS have?

A

Enzymatic activity constitutive – active all the time

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18
Q

What kind of expression does inducible NOS have?

A

Expression inducible
When induced they have a longer lasting effect
Produce nanomoles of nitric oxide

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19
Q

When activated what does inducible NOS form?

A

Nanomoles of nitric oxide

20
Q

Where is inducible NOS expressed?

A

Macrophages and Kupffer cells
Neutrophils
Fibroblasts
Vascular smooth muscle and endothelial cells

21
Q

What is the effect of nitric oxide in the vasculature?

A
  1. Autonomic nerves release Ach - acts on eNOS
  2. eNOS release nitric oxide - causes surrounding smooth muscle to relax - vasodilation
  3. NO inhibits platelet aggregation and vascular smooth muscle proliferation
    a. Anti-atherosclerotic
22
Q

How is nitric oxide induced?

A
  1. Acetylcholine activates nitric oxide synthase (cNOS) in endothelial cells
  2. NOS generates nitric oxide from arginine
  3. Nitric oxide activates the production of cGMP
23
Q

What does nitric oxide activate the production of?

A

cGMP

24
Q

How does nitric acid activate the production of cGMP?

A
  1. cGMP
  2. cGMP – dependent protein kinase
  3. Myosin light chain phosphatase
  4. Myosin light chain
25
Q

What is the effect of nitric oxide in the brain?

A
  1. In the CNS, nNOS is tethered close to NMDA-type glutamate receptors
  2. This means it can respond to Ca2+ increases near the open channels
    a. Implications for synaptic plasticity
  3. Glutamate is produced by a presynaptic terminal and this activates glutamate receptors
  4. Especially NMDA receptors which stimulate the nitric oxide pathway
  5. The nitric oxide produced travels to the presynaptic terminal
  6. It increases the production of glutamate - creating the state of long-term potentiation
26
Q

What is the role of nitric oxide in the immune system?

A

Kills bacteria and parasites
Induces programmed cell death
Triggers inflammatory diseases when overproduced in lungs and intestines
- Rheumatoid arthritis, Crohn’s disease and asthma
Role in tumour apoptosis and necrosis

27
Q

What does iNOS in inflammatory cells use nitric oxide for?

A

Use nitric oxide as a cytostatic and cytotoxic agent

Involves much higher amounts of NO

28
Q

How was nitroglycerine use as a pharmaceutical?

A

100 yr treatment for angina - pain due to inadequate blood flow to heart
Nitroglycerine breaks down in vivo to generate nitric oxide which relaxes blood vessels
- Decreases load on heart
- Increases heart blood supply

29
Q

What is dynamite made of?

A

Nitroglycerine + fine clay as a stabiliser

30
Q

What does nitric oxide activate in smooth muscle?

A

Guanylyl cyclase which leads to formation of cGMP

31
Q

How can too much cGMP in a cell be fixed?

A

Phospho-diesterase 5

Converts cGMP to GMP sing cGMP dependent protein kinase

32
Q

How does Viagra work?

A
  1. Inhibits phosphodiesterase 5
  2. Leads to less breakdown of cGMP
  3. Smooth muscles constricting blood vessels relax
  4. More blood flow
33
Q

What are some examples of the nuclear receptor superfamily?

A 
Cortisol 
Estradiol 
Testosterone 
Thyroxine 
Vitamins D3
Retinoic acid
34
Q

How many domains do nuclear receptors have?

A 
3
Transcription activating domain 
DNA binding domain 
Regulatory binding domain 
- Binds to ligands releasing inhibitory protein
35
Q

How do nuclear receptors go from their active state to inactive state?

A
  1. Inhibitory proteins hold the receptors in inactive state
  2. Binding to ligand removes inhibitors leading to a conformational change
  3. Receptors now interact with coactivators to direct transcription
    The effects of the ligands are modified in different tissues by the expression of different coactivators
36
Q

What is the structural organisation of the estrogen receptor?

A

DNA binding domain consists of Zinc Fingers

Each finger binds a specific DNA sequence

37
Q

Examples of symmetric homodimers

A

Glucocorticoid and estrogen receptors

38
Q

Examples of heterodimers

A

Vitamin D, thyroid hormone, and retinoic acid receptors

39
Q

How do symmetric homodimers bind?

A

Bind as symmetric homodimers to an inverted repeat DNA site

40
Q

How do heterodimers bind?

A

Bind as heterodimers to direct repeat sites

RAR:RXR or VDR:RXR

41
Q

Where are homodimeric receptors found?

A

Anchored in the cytoplasm by inhibitor proteins in the absence of ligand
- E.g. Hsp90
Hormone binding causes release of inhibitor proteins allowing entry to nucleus

42
Q

Where are heterodimaeric receptors found?

A

Located exclusively in nucleus

43
Q

How do heterodimeric receptors act in the absence of ligands?

A

Act as repressors in the absence of ligand - recruitment of histone deacetylases

44
Q

How do heterodimeric receptors act in the presence of ligands?

A

Act as activators in the presence of ligand - recruitment of histone acetylases

45
Q

Early primary response to steroid hormone – 1-6 hours

A

Steroid-hormone receptor complexes activate transcription of primary response genes
Some of these genes will encode transcription factors
Induced synthesis of a few proteins

46
Q

Delayed secondary response to steroid hormones – 6-48 hours

A

Primary response protein shuts of primary response genes and turn on secondary response genes
Induced synthesis of secondary response proteins

Cell and Molecular (24 decks)

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