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BMS 242 - Advanced Cell and Molecular > Signalling via intracellular receptors > Flashcards

Signalling via intracellular receptors Flashcards

1
Q

Which signals can pass through the membrane to interact with intracellular receptors?

A
  • Small molecules

- Hydrophobic molecules

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2
Q

What do cell-surface receptors do?

A

Bind hydrophillic signals (can’t cross the membrane) and TRANSDUCE the signals into an intracellular response

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3
Q

How do molecules that bind intracellular receptors get into the cell?

A

Diffuse straight through the membrane
OR
Use carrier proteins

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4
Q

Which 4 molecules bind to nuclear receptors?

A

1) Steroid hormones (testosterone, cortisol, estradiol)
2) Thyroid hormones (thyroxine)
3) Retinoids (retanoic acid - Vitamin A)
4) Vitamin D

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5
Q

What gases bing to intracellular receptors?

A 
Nitric oxide (NO)
Carbon monoxide (CO)
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6
Q

What are 3 properties of NO?

A

1) Very small (only 2 atoms)
2) Gaseous
3) Free radical

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7
Q

What is a free radical and what can it do?

A

Unpaired electron in the outer shell
Very reactive
Can damage other proteins

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8
Q

What are other nitric gases that are quite stable?

A 
Nitrogen Dioxide (NO2)
Nitrous Oxide (N2O)
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9
Q

How is NO made?

A
  • Substrate of L-arginine (an amino acid)
  • 2 successive oxidations
  • Producing L-citrulline, NO and water
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10
Q

What enzyme produces NO from L-arginine?

A

NOS (Nitric oxide synthase)

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11
Q

What is important about NOS?

A

Comes in various varieties, which are specific for function

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12
Q

What is cNOS?

A

Constitutive NOS - when transcribed in the cell they are expressed all of the time

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13
Q

How is the enzymatic activity of cNOS induced?

How long does the activity last for?

A

By Ca2+/Calmodulin

Activity is short-lived

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14
Q

How much NO does cNOS produce?

A

Very small amounts (picomoles)

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15
Q

What are the 2 representatives of cNOS?

A

eNOS (endothelial)

nNOS (neural)

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16
Q

Where is eNOS present?

A

At the CELL MEMBRANE

Expressed in:

  • Endothelium
  • Cardiac myocytes
  • Osteoblasts/osteoclasts
  • Platelets
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17
Q

What is nNOS present?

A

In the CYTOSOL

Expressed in:

  • CNA
  • NANC neurons
  • ENS
  • Retina
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18
Q

What is eNOs important in?

A

Vasculature

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19
Q

What is iNOS?

A

Inducible NOS

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20
Q

How is iNOS different to cNOS?

A

Expression is inducible but the enzymatic activity is constitutive

Where as cNOS - the expression is constitutive but the enzymatic activity is regulated

iNOS also has a long-lasting effect and produces more NO

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21
Q

When is iNOS transcriptionally induced?

A

In response to pathological stimuli (LPS, IFN-g, IL-1)

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22
Q

Where is iNOS expressed?

A
  • Macrophages and Kupffer cells
  • Neutrophills
  • Fibroblasts
  • Vascular smooth muscle and endothelial cells
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23
Q

What activates eNOS?

What does this cause?

A

Ach release from autonomic nerve terminals

Causes:
1) eNOs to act on L-arginine to make L-citrulline and NO

2) NO binds to guanylyl cyclase and converts GTP to cGMP
3) cGMP then binds to cGMP-dependant protein kinase (PKG) to acitvate it
4) PKG acts on myosin light chain phosphatase
4) MLCP removes phosphate from myosin light chain to cause RELAXATION OF THE MUSCLE

24
Q

What does NO released from eNOS inhibit?

A

Platelet aggregation and vascular smooth muscle proliferation

25
Q

In the CNS, what is nNOS tethered close to in the cytosol?

Why?

A

NMDA-type glutamate receptor on the postsynaptic membrane

So that nNOS can respond to Ca2+ increases near the open channels

26
Q

What is the process of nNOS activation and what does this cause?

A

1) Glutamate produced by presynapse
2) Glutamate bind NDMA glutamate receptor - releases Ca2+
3) Ca2+ acitvates nNOs - synthesises NO
4) NO diffuses into the presynaptic terminal to activate glutamate production
5) Forms a positive feedback loop

27
Q

What does the positive feedback loop of NO in the brain cause?

A

Long-term potentiation and memory

synaptic plasticity

28
Q

What does NO do in the immune system?

A
  • Kills bacteria an parasites

- Programmed cell death

29
Q

What does iNOS do?

A

Triggers death at very high levels of NO

Cytostatic and cytotoxic agent

30
Q

What causes rheumatoid arthritis, Crohn’s disease and asthma?

A
  • Inappropriately elevated levels of NO - causing inflammatory responses
  • Necrosis
31
Q

What can nitroglycerine be used as? (2 things)

A

1) Dynamite (when mixed with fine clay)

2) Angina treatment

32
Q

How does nitroglycerine treat angina?

A

Administered as a spray

Rapidly breaks down in vivo to generate NO - relaxes blood vessels and lowers blood pressure

33
Q

What does PDE5 do?

A

Recycles cGMP into GMP and then GTP, even when there is NO present (causes GTP–>cGMP)

This prevents the build up of cGMP (which normally binds to cGMP-dependant protein kinase to produce smooth muscle contraction)

34
Q

What is an inhibitor of PDE5?

What is the consequence of this?

A

Viagra

  • cGMP builds up
  • Smooth muscles relax
  • More blood flow to the blood vessels
35
Q

What is PDE5?

A

Phosphodiesterase 5

36
Q

What makes the signalling molecules that bind to nuclear receptors hydrophobic?

A

Many carbon rings

37
Q

What is the structure of a nuclear receptor?

A

1) Transcriptional activating domain
2) DNA-binding domain
3) Regulatory domain/ligand binding domain

38
Q

What does the regulatory domain of a nuclear receptor bind?

A

1) Inhibitory proteins

2) Bind the ligand

39
Q

What does binding of the regulatory domain to an inhibitory protein do? (nuclear receptor)

A

Holds the receptor in an inactive state

40
Q

What does binding of the regulatory domain to the ligand do? (nuclear receptor)

A
  • Removes the inhibitory protein
  • Resulting in a conformational change
  • Binding coactivators
41
Q

What drives the different effects between ligands in different tissues, in regards to a nuclear receptor?

How?

A

Coactivators:

  • Nuclear receptors are the same in each tissue
  • Coactivators are tissue specific and modify the activit of the ligand
42
Q

What does the DNA binding domain of the estrogen receptor consist of?

A

Zinc fingers

43
Q

What are the biding sites divided into?

What receptors bind here?

A

Inverted repeat (palindromic) - homodimers

Direct repeat (tandem) - heterodimers

44
Q

How do glucocorticoid and estrogen receprtors bind to DNA?

A
  • Bind as symmetric homodimers to an inverted repeat DNA site
  • Bind palindromic sequence
  • 2 proteins face each other (mirror image of binding sequence)
  • Sequence separated by 3 nucleotides
45
Q

How do receptors for Vitamin D, retanoic acid and thyroid hormone bind to DNA?

A
  • As heterodimers to tandem repeats
46
Q

What do the nuclear family members that form heterodimer bind to?

What is important about this factor

A

RXR (retanoid X receptor)

RXR is present and active all of the time, but can only activate transcription when there is a pairing of the second receptor

47
Q

What is important in the response element of heterodimers?

A

The spacing between direct repeats

48
Q

Where are homodimeric receptors found?

Why are they found here?

A

In the cytoplasm in the absence of the ligand (in their inactive state)

Anchored to the cytoplasm by inhibitor proteins, including Hsp90

49
Q

What does hormone binding to homodimeric receptors cause?

A

Release of inhibitor protein - allowing them to enter the nucleus

50
Q

Where are heterodimeric receptors located?

A

Exclusively in the nucleus at their binding site

51
Q

How do heterodimeic receptors act in the absence and presence of the ligand?

How do they do this?

A

Absense - Repressors by recruiting histone deacetylases

Presence - activators by recruiting histone acetylases

52
Q

How do the nuclear receptor family function?

How is this different to insulin receptors?

A

Entirely by transcriptional regulation

Insulin receptors also have a faster response - translocation

53
Q

What is the response of nuclear receptors broken down into?

Describe each stage

A

1) Early primary response
- Receptors activate transcription of primary response genes

2) Delayed secondary response
- Some primary response genes encode transcription factors and activates secondary response genes to create secondary response proteins

54
Q

What are primary response genes?

A

Genes that are directly activated by the nuclear receptor

55
Q

When does the early response occur?

A

1-6 hours after activation

56
Q

When does the delayed response occur?

A

6-48 hours after activation

BMS 242 - Advanced Cell and Molecular (24 decks)

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