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Intercal - Advanced molecules, membranes and cells > Calcium Homeostasis 2 > Flashcards

Calcium Homeostasis 2 Flashcards

1
Q

What activates the ryanodine receptor

A

Calcium - when high calcium conc is cytoplasm this opens the ryanodine receptor to trigger more calcium release from cytoplasmic reticulum and increase the cytosolic calcium

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2
Q

Where is the ryanodine receptor mostly found

A

Cardiac and muscle cells

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3
Q

How does an action potential trigger the ryanodine receptor to open

A

AP –> voltage-gated calcium channels open in T tubule of cell membrane –> T-tubule interacts directly with ryanodine receptor in ER/SR –> Opening of Ryr-sensitive calcium release channels –> calcium release into cytoplasm

Essentially a positive feedback mechanism as initiated by calcium and increases calcium

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4
Q

What happens when calcium levels get too high (mM conc)

A

This inactivates RyR so the signal is turned off - a protective mechanism to prevent extremely high calcium levels

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5
Q

What is the ryanodine receptor similar to

A

IP3R - tetramer and large with a central pour.

Ryanodine twice as big though

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6
Q

What effect does ryanodine have on the ryanodine receptor and what is important about this

A

Low conc - permanently open but subconductance state

High conc - fully block channel

THIS IS NOT PHYSIOLOGICAL

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7
Q

Where is ryanodine receptors important

A

Malignant hyperthermia

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8
Q

Give some features of malignant hyperthermia

A

Inherited disorder - 1 in 15,000
Caused by volatile anaesthetic (halothane)
Due to defect in RYR1 calcium channel release - causes increase sensitivity to caffeine and calcium and greater channel conductance and longer opening times of channels

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9
Q

What is the pathophysiology of malignant hyperthermia

A

Uncontrolled increase in sarcoplasmic reticulum calcium concentration which increases the aerobic and anaerobic metabolism.

As a result, this causes an increased body temperature, acidosis and muscle rigidity leading to death

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10
Q

How is malignant hyperthermia treated

A

Dantrolene - a RYR channel blocker

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11
Q

What are the different features of IP3 and ryanodine when considering skeletal muscle

A

IP3 - minor
Ryanodine - major

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12
Q

What are the different features of IP3 and ryanodine when considering smooth muscle

A

IP3 - dominant
Ryanodine - minor

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13
Q

What are the different features of IP3 and ryanodine when considering caffiene

A

IP3 - no action
Ryanodine - opener

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14
Q

What are the different features of IP3 and ryanodine when considering ruthenium red

A

IP3 - no action
Ryanodine - blocker

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15
Q

What are the different features of IP3 and ryanodine when considering heparin

A

IP3 - inhibitor
Ryanodine - no action

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16
Q

What are the different features of IP3 and ryanodine when considering dantrolene

A

IP3 - no action
Ryanodine - blocker

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17
Q

What is the role of cyclic ADP-ribose (cADPR)

A

Finds and binds to ryanodine receptors on the endoplasmic reticulum for calcium release

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18
Q

How does NO activate cADPR

A

Produced by nitric oxide activated G-cyclase to form cGMP which activates the ADP-ribosyl cyclase to form the cADPribose which binds to RyR to release calcium from the ryanodine store

19
Q

What are calcium microdomains

A

Rapid, small and localised different concentrations of calcium across the cell

20
Q

How do calcium microdomains occur

A

Via localized one or a few calcium release or calcium intracellular entry channels

21
Q

What are unitary events

A

Sparks of calcium rising which are due to RyR receptors

These are spontaneous with no other channels involved, due to local balance of cytoplasmic and SR calcium concentrations

22
Q

What are evoked events

A

Due to RyR activation induced via calcium entry into cells via voltage gated calcium channels (as spoke about previously)

23
Q

What is the role of these calcium sparks

A

Unsure but may prime or initiate larger calcium events

24
Q

What is calmodulin

A

When calcium binds it activates it and mediates many calcium ion signalling functions.

25
Q

What is an EF-hand

A

Calmodulin binds 4 calcium ions and at each site, oxygen atoms bind from glutamate and aspartate to form a helix-loop-helix motif called an EF-hand

26
Q

What is the structure of calmodulin

A

Dumbell shaped - 4 helix-loop-helix motifs 2 at each end of calmodulin

27
Q

How does calmodulin work

A

Calcium-binding promotes a conformational change that exposes hydrophobic pockets along the 2 lobes which provide binding sites for the target enzymes

28
Q

Give some calmodulin target proteins

A

Calcineurin - a phosphatase
NOS
Calpains
Calcium-magnesium ATPase pump
CaM-kinase - transcription factor

29
Q

Give the three methods for handling larger calcium loads in calcium homeostasis

A

Mitochondria
Calcium binding proteins
Na/Ca exchanger

30
Q

Give the three methods for handling smaller calcium loads in calcium homeostasis

A

ER/SR uptake
Calcium binding proteins
ATP-dependent transport

31
Q

What are calcium puffs

Wider reading - Yao et al 1995

A

Similar to calcium sparks but from IP3R in the ER - Localised calcium increase inside the cell

32
Q

What is the link of microdomains and ROS

Wider reading - Brookes et al 2004

A

Microdomains in the mitochondria can increase resp activty and therefore increase ROS production by respiratory chain

33
Q

What happens to the RYR in redox stress

WIDER READING - Xia et al 2000

A

Its sulfhydryl groups were shown to have a well-defined redox potential in skeletal muscle SR. Thus, under mild oxidative stress, relatively small changes in the cellular redox potential can contribute to significant stimulation of the ryanodine receptor

34
Q

What is central core disease and why is it important

WIDER READING - McCarthy et al 2000

A

Autosomal dominant congenital myopathy with variable presentation but progressive proximal weakness and delayed motor development is common.

Patients more susceptible to milignant hyperthermia too.

90% linked to RYR1 mutation - causes impaired calcium influx so impaired intracellularl signalling and muscle contraction

35
Q

How was dantrolene shown to help in polymorphic ventricular tachycardia

WIDER READING - Kobayashi et al 2010

A

Stopped leaky calcium RyR2 cardiac receptors from leaking in arrhythmic effect knock in mice (leaky RyR2) which in turn significantly decreased polymorphic ventricular tachycardia when these mice exercised with ephinephrine.

36
Q

What is the role of magnesium in dantrolene

WIDER READING - Choi et al 2017

A

Key to working - high affinity of Mg to RyR causes RyR to shut therefore its needed for dantrolene
Believed that dantrolene helps Mg binding.

Explains why it works in malignant hypothermia (as increase in Mg during this time through MgATP hydrolysis) but not on individual RyR1 receptors

37
Q

How does caffeine effect the RyR

WIDER READING - Kong et al 2008

A

Monitoring of endoplasmic reticulum luminal Ca2+ revealed that caffeine reduced the luminal Ca2+ threshold at which spontaneous Ca2+ release occurs by RyR.

Therefore caffeine reduces luminal calcium threshold but had no effect on cytosolic threshold.

Important as this decrease in threshold in luminal calcium trigger release is also seen in pro-arhythmic methylxanthines linke theophylline so it may share same arrhythmogenic mechanism

38
Q

Why is calmodulin so flexible

WIDER READING - Yamniuk et al 2004

A

Structural variabilty when bound to different targets
Flexible center allows for wrapping
Hydrophobic so attracts many targets

39
Q

How many target proteins can bind to calmodulin

WIDER READING - no reference

A

300

40
Q

What is the role of calmodulin in smooth muscle

WIDER READING -Tansey 1994

A

Calmodulin activates myosin light chain kinase which phosphorylates the myosin light chain to cause cross-briding and smooth muscle contraction.

Calmodulin relies on calcium so this is why smooth muscle contraction is calcium dependent

41
Q

What is the role of calmodulin on the RyR and how does this effect muscle contraction

WIDER READING - Walsh 1994

A

Controlling movement of Ca2+ across sarcoplasmic reticiulum membranes.

the ryanodine receptor of the sarcoplasmic reticulum, can be inhibited by calmodulin bound to calcium, thus affecting the overall levels of calcium in the cell

42
Q

What role does calmodulin have in glucose metabolism

WIDER READING - Nishizawa et al 1988

A

Calmodulin plays an important role in the activation of phosphorylase kinase, which ultimately leads to glucose being cleaved from glycogen by glycogen phosphorylase.

43
Q

What role does calmodulin have in memory

WIDER READING - Lledo 1995

A

Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a crucial role in a type of synaptic plasticity known as long-term potentiation (LTP) which requires the presence of calcium/calmodulin. CaMKII contributes to the phosphorylation of an AMPA receptor which increases the sensitivity of AMPA receptors.[38] Furthermore, research shows that inhibiting CaMKII interferes with LTP.

Intercal - Advanced molecules, membranes and cells (31 decks)

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