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BS32028 > Regulating Intracellular Calcium > Flashcards

Regulating Intracellular Calcium Flashcards

1
Q

In what time frames do the following events occur?
- Synaptic vesicle release
- Excitation-contraction coupling
- Smooth muscle relaxation
- Excitation-transcription coupling
- Gene transcription
- Fertilisation

A
  • Synaptic vesicle release (ms)
  • Excitation-contraction coupling (ms)
  • Smooth muscle relaxation (ms-sec)
  • Excitation-transcription coupling (min-hours)
  • Gene transcription (hours)
  • Fertilisation (hours)
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2
Q

What happens if there is too little intracellular calcium activity?

A

Isolation of cell, decreased survival chance

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3
Q

What happens if there is too much intracellular calcium activity?

A

Seizures, toxicity, cell death

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4
Q

What is the distribution of calcium in the body?

A

Ca comprises 1.5%-2% of total body mass
99% is in the bone, but this can change significantly
Serum Ca is <0.1% of total

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5
Q

What are the 3 kinds of Ca homeostasis, and the amount of Ca implicated?

A

Cellular Calcium (1-10 to 50 nM)
Serum Calcium (1.3 mM)
Bone calcium (continuously changes)

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6
Q

How does calcium transmit information?

A
  • The intracellular calcium concentration goes from nanomolar to micromolar
  • Ca can then bind to specific proteins in the cell (at a lower concentration they wouldn’t have)
  • Ca occupancy results in 3D conformational change and changes in activity
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7
Q

Intracellular calcium concentration at rest?

A

< 10^-7 M

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8
Q

Extracellular calcium concentration at rest?

A

~ 10^-3 M

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9
Q

ER calcium concentration at rest?

A

~ 10^-3 M

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10
Q

Why and how do cells maintain a low intracellular Ca concentration?

A

So that a little Ca entering the cytosol will cause a large increase in concentration

They maintain this by actively pumping Ca out of the cytosol (Na/Ca exchanger, PM Ca ATPase), and pumping Ca into the ER and mitchondria (SERCA, Ca binding molecules in cytoplasm, Ca pump on mitochondria)

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11
Q

Is free or stored Ca regulated?

A

Free

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12
Q

What are the 6 major pathways for cellular Ca increase?

A
  • Voltage gated Ca channels (VGCC)
  • Receptor operated Ca channels (ROCC)
  • Na/Ca exchanger
  • Ca ATPase of sarco(endo)plasmic reticulum
  • Ca ATPase of plasma membranes (in cell)
  • Ca releasing channels of the SR or ER (in cell)
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13
Q

How is calcium released from intracellular stores?

A

Ligand binds to GPCR linked to G-alpha-q -> activates PLC -> PLC catalyses PIP2 into IP3 and DAG > IP3 binds to IP3 Receptors (IP3R) on ER surface > calcium is released into cytosol

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14
Q

What is the structure of the IP3 Receptor?

A
  • A macromolecular complex: monomers form functional tatramers (4 subunits)
  • Have ligand binding domain, regulatory domain, and channel domain
  • 6 membrane spanning regions: M1-M6
  • Four binding sites for IP3 (one on each subunit)
  • Has an IP3 sensor
  • Has a calcium release channel
  • At least 3 subtypes exist (1, 2, and 3)
  • IP3R1 is the main type in the brain (cerebellum)
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15
Q

What is ‘store-operated calcium entry’?

A

Depletion of intracellular calcium stores activates calium entry to subsequently refill the emptied calcium stores

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16
Q

How does store-operated calcium entry work?

A

Two key components; a sensor of calcium store depletion (STIM - stromal interacting molecule) and a channel that when activated by the sensor allows Ca into the cell (ORAI proteins)

STIM proteins on the ER membrane oligomerize and move to areas of the ER that are close to the plasma membrane, where they activate ORAI channels and allow Ca entry

17
Q

What are agents that can prevent Ca resequestration and thereby cause store depletion?

A

Thapsigargin and cyclopiazonic acid (CPA)

18
Q

What are ORAI proteins?

A

Form Ca pore on plasma membrane
Tetrameric proteins
Coded for by 3 genes; ORAI1, ORAI2, ORAI3

19
Q

What are STIM proteins?

A

Proteins that sense when the intracellular Ca store is depleted
Coded for by 2 genes; STIM1 (responds to agonist-mediated Ca store depletion) and STIM2 (sensor of basal ER Ca levels)

Ca binds with low affinity to the EF-hand domain of STIM proteins when the ER store is full, and releases itself when depleted, leading to activation of the CRAC channel (unbound STIM leads to CRAC channel activation + entry of Ca regardless of whether the ER store is depleted)

STIM1 binds to the microtubule plus-end tracking protein EB1 (end bnding protein 1) and associates with tubulin at the growing plus-end of microtubules. STIM1 can thus cover long distances within the cell

20
Q

What happens if there is an increase in mitochondrial Ca?

A

Increase in mitochondrial Ca causes mitochondria to stimulate ATP production

21
Q

What happens when the mitochondrial Ca capacity is exceeded?

A

The opening of a high-conductance channel (the mitochondrial permeability transition pore (PTP)) is induced, which leads to collapse of the proton gradient, and ATP production, and to a loss of mitochondrial membrane integrity and some forms of cell death

22
Q

Mitochondrial Ca homeostasis and cell death?

A

Ca accumulation by mitochondria is common in necrotic and apoptotic cell death, and may induce apoptosis

23
Q

Entry and exit of Ca into/out of the mitochondria

A

Mitochondria can maintain low matrix Ca concentrations at rest, but can also quickly increase conc when cytosolic Ca is increased

Outer mitochondrial membrane (OMM) is highly permeable to Ca due to abundant expression of voltage-dependent anion channels (VDAC)

Ca entry across the IMM is dependent on electrical + chemical gradients
Ca exit acroos the IMM mediated by Na dependent and independent pathways

24
Q

Mitochondria as cytosolic Ca buffers

A
  1. Mitochondrial Ca buffering regulates the activity of Ca channels
    - Mitochondria quickly remove Ca ions from mouths of open channels on the ER, SR, or plasma membrane
    - Coordinates subsequent IP3-induced rises in cellular Ca into single propagating Ca waves of lower frequency and higher amplitude
    - Removal of Ca from the vicinity of IP3 inhibits channel opening, but relieves Ca-mediated inhibition of open channels
  2. Control of Ca gradients through mitochondrial positioning
    - Mitochondria may block off a certain area in a cell before which there isn’t much Ca and after which there is
25
Q

What is the spatial signalling of Ca like?

A

Ca diffusion throughout the cell is hindered by immobile buffers; Ca increases can therefore be highly localised
OR, Ca can propagate as a wave through the cell (ie to communicate signal to nucleus)

26
Q

Why does Ca enter the cell in waves?

A

Sustained Ca elevations kill cells (ie glutamate neurotoxicity)
Frequency of waves encodes stimulus (higher frequncy = stronger stimulus)

27
Q

Fertilisation of an egg by a sperm triggers an increase in cytosolic Ca. What are the 3 major types of Ca channels utilised here?

A
  1. Voltage dependent Ca channels on plasma membrane
  2. IP3-gated Ca release channels on ER membrane
  3. Ryanodine receptors on ER membrane
28
Q

What is the open probability of IP3 receptors like?

A

Ca released by one IP3R increases the probability of neighbouring IP3Rs opening (self-amplifying release mechanism)
Very high Ca concentrations can inhibit IP3Rs and prevent Ca release

29
Q

What is the IP3 receptor structure?

A

Has 3 binding sites: IP3 binding site, Ca activating binding site, Ca inhibiting binding site

Channel opens upon binding of IP3, and Ca to the activating site
Binding of Ca to the inhibiting site closes the channel (binding here occurs slower and with lower affinity than activating site)

In cells, they form clusters of 1-30 channels separated by 1-3 micrometers
Opening of a single channel - blip
A few channels - puff
>7 - wave

A local Ca signal is one of these clusters
A global Ca signal is a few adjecent clusters being activated

30
Q

What is meant by itercellular oscillations with reference to Ca signalling?

A

One cell is stimulated to produce PLC > IP3 > Ca

This cell sends intercellular signals in the form of IP3 signals to its neighbouring cells, the signal decreasing in strength the further along it goes

The cell also sends out extracellular messengers that activate the GPCR so that PLC gets activated

This leads to release of Ca from intracellular stores in adjacent cells as well
- Happens in beta cells to synchronise Ca and release insulin

31
Q

What is calmodulin, and what is its structure?

A

A Ca binding protein

  • Has 4 Ca binding sites (EF-hand motifs)
  • No intrinsic enzymatic activity
  • Modulates activity of cellular targets
  • Ca binding increases its affinity for target enzymes by exposing hydrophobic surfaces
32
Q

What is the structure of Calmodulin Dependent Protein Kinase II (CaMKII)?

A

CAMKII has: catalytic domain - auto-inhibitory domain - CaM - subunit association

The auto-inhibitory domain occupies and blocks the catalytic site

There are high levels of CaMKII in the neurons - concentrated in the postsynaptic density (PSD)
Also play an important role in the induction of long term potentiation (LTP) (a cellular correlate of learning and memory)

There are 10-12 subunits, in the shape of a flower almost, with the NH2 terminals pointing outwards and the COOH terminals inwards

33
Q

What is the function of Calmodulin Dependent Protein Kinase II (CaMKII)?

A

Ca/Calmodulin complex removes the auto-inhibitory domain > autophosphorylation > activation of CaMKII

CaMKII = inactive > Ca/Calmodulin complex binds = active > auto-phsophorylation of CaMKII = fully active > Ca dissociates > calmodulin dissociates (~10 sec after Ca) > CaMKII = 50-80% active > protein phsophatase dephosphorylates CaMKII > CaMKII = inactive

34
Q

What are the targets of calcium if it entered through the NMDA receptor?

A

Ca forms Ca/Calmodulin complex
Complex targets CaMKII + calcineurin

35
Q

What is the role of CaMKII in LTP?

A
  1. Ca enters cell through active NMDA receptor
  2. Targets CaMKII
  3. CaMKII phosphorylates AMPA subunits (causes it to have larger current - contributes to short-term LTP (~30 min))
  4. CaMKII initiates addition of AMPA receptors to synapse (contributes to longer lasting LTP)
  5. Helps regulate processes that re-arrange + enlarge cytoskeleton
36
Q

What is the role of Calcineurin in long-term depression (LTD)?

A
  1. Ca flows through activated NMDA receptor
  2. Targets calcineurin (or protein phosphatase 2B), a Ca/CaM-dependent protein phosphatase
  3. Calcineurin regulates phophatase 1 (inhibition of calcineurin blocks induction of LTD) (LTD results from removal of AMPA receptors by endocytosis)

BS32028 (4 decks)

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