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MCB > IP3 and Calcium Release > Flashcards

IP3 and Calcium Release Flashcards

1
Q

Where is the majority of the IP3 receptor?

A

In cytosol

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2
Q

What is the structure of the IP3 receptor?

A
  • Tetrameric homodimer
  • Small hole in centre where Ca2+ moves
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3
Q

What is the Hill coefficient of IP3 receptor and why?

A
  • 3 because 3 molecules of IP3 need to bind for the channel to go into an intermediate state
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4
Q

What is required for the IP3 receptor to go from an intermediate to an open state?

A

Requires free intracellular Ca2+ to bind

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5
Q

What happens to the IP3 receptor when [Ca2+] intracellular increases?

A

It inhibits the activity of the IP3 receptor and stops the flux of Ca2+ out of the ER

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6
Q

What is the relationship between probability of an open IP3 receptor and concentration of intracellular calcium?

A
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7
Q

Why do Ca2+ oscillations occur due to IP3?

A
  • Because the agonist IP3 is still present a point is reached where the receptor is resensitised so can now generate the next ‘spike’
  • This is why amplpitude is the same every time
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8
Q

What is required to sustain Ca2+ fluxes and why?

A
  • Ca2+ must enter the cell because each time Calcium goes back to a resting level some is lost to out of the cell
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9
Q

How does calcium influx occur in sustained calcium signalling?

A
  • Dissociation of Ca2+ occurs away from lumenal side of STIM1
  • STIM1 forms digomeric assemblies which assemble in cortical ER and couple to Orai1
  • Then opens the Orai1 channel and allows Ca2+ to come into cytoplasm
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10
Q

Where is STIM1 located?

A

ER-resident integral protein

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11
Q

What is the function of STIM1?

A

Senses the ER luminal free Ca2+ concentration

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12
Q

What is the function of Orai1?

A

It is a Ca2+ influx channel

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13
Q

What structure does STIM1 usually have?

A

Dimer locked in dimer conformation

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14
Q

What causes [Ca2+] to drop in ER lumen?

A

Stimulation with IP3

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15
Q

How does IP3 affect STIM1?

A
  • IP3 causes [Ca2+] in ER lumen to drop as fluxing to cytosol causes dissociation of Ca2+ away from lumenal side of STIM1 which alters STIM1 structure
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16
Q

What happens to STIM1 and Orai1 when ER refills?

A

STIM1 goes back to dimeric state which stops coupling to Orai1 and channel shuts

17
Q

What is the structure of Orai1?

A
  • Hexamer of 6 Orai subunits arranged around a central axis
  • Gated central core which allows Ca2+ to flux in
18
Q

How does STIM1 cause Orai1 to open and Ca2+ enter the cell?

A
  • STIM1 reconfigures cytoplasmic structure of Orai1 channel and pulls apart from helices making up pore of channel
  • Conformational coupling
19
Q

Where are the Ca2+ binding sites located on calmodulin?

A

On amino and carboy termini

20
Q

What happens to calmodulin when Ca2+ is bound?

A
  • Alters conformation
  • Allows calmodulin to bind specifically to a variety of target proteins, locking them into certain conformations and allowing them to be calcium responsive
21
Q

What is the structure of Calmodulin-dependent PKII?

A
  • 6 kinase subunits
22
Q

How is calmodulin dependent PKII activated?

A
  • amino-carboxy terminal end of calmodulin can bind to the regulatory segment
  • this catches the kinase domain when it ‘pops out’ and activates it
  • Kinase phosphorylates itself and neighbouring subunit to activate the enzyme
23
Q

How is the active state of calmodulin dependent PKII further stabilised?

A

By calmodulin locking kinases

24
Q

How is calmodulin dependent PKII deactivated?

A
  • When [Ca2+] decreases calmodulin dissassociates and becomes partially active
  • Phosphatases remove phosphates
25
Q

What happens to activity of calmodulin dependent PKII at high calcium concentrations?

A
  • Phosphatases don’t have enough time to deactivate enzyme before Ca2+-calmodulin spike
  • Build up of activity
26
Q

where is the IP3 receptor located?

A

between the ER lumen and the cytosol

27
Q

Where is STIM1 located?

A

In the ER

28
Q

Where is Orai1 located?

A

In the plasma membrane

29
Q

How can Ca2+ leave the cell?

A
  • PMCA
  • Sodium Calcium exchanger
30
Q

How does STIM1 activate Orai1?

A

Binding pulls the helices apart and opens the channel to allow Ca2+ to enter

MCB (28 decks)

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