M&R Control of cytosolic calcium

Question 1

How do action potentials open calcium channels?

Answer 1

Depolarisation opens the voltage gated Ca2+ channels,

Question 2

What makes voltage gated calcium channels different to other voltage gated channels?

Answer 2

Voltage gated channels are very structurally diverse - there are different isoforms depending on the tissue type

A blocker that blocks one channel may not block another, therefore blocking one channel can have a localised effect

Question 3

How does calcium cause neurotransmitters to be released?

Answer 3

Calcium enters the neurone
Calcium binds to SYNAPTOTAGMIN 
The vesicle moves close to the membrane
SNARE COMPLEX makes a fusion pore
The transmitter is released through this pore

The transmitter produces an END-PLATE POTENTIAL which will raise the muscle above threshold.

Question 4

Describe the actions of 2 nicotinic receptor blockers

Answer 4

1. TUBOCURARINE is a competitive blocker that causes paralysis
   Tubocurarine binds to nAChR whilst closed, preventing ACh binding.
2. SUCCINYLCHOLINE is a depolarising blocker that is used in surgery to induce paralysis
   Causes a maintained depolarisation, adjacent Na+ channels will not be activated due to accommodation

Question 5

What is the difference between nAChR and mAChR?

Answer 5

Nicotinic ACh receptors produce fast depolarisation because it is a ligand gated ion channel

Muscarinic ACh receptors produce slower depolarisation because they are G-protein coupled receptors

Question 6

Explain the biochemical basis of Myesthenia Gravis

Answer 6

Autoimmune disease targeting nAChR
Antibodies degrade nAChR on postsynaptic membrane of skeletal muscle
Endplate potentials are reduced in amplitude leading to profound muscle weakness and fatigue

Question 7

How is the calcium conc gradient set up and maintained?

Answer 7

Ca2+ is expelled from the cell via:

1. Ca2+ ATPase (high affinity, low capacity)
   Ca2+ binds to CALMODULIN
   The calmodulin-Ca2+ complex binds to Ca2+ ATPase
   Ca2+ removed from the cell
2. NCX (low affinity, high capacity)
   Na+ gradient used to drive the removal of Ca2+

There are calcium buffers
Intracellular calcium stores

Question 8

How is intracellular Ca2+ returned back to basal levels?

Answer 8

The signal is terminated
Ca2+ is removed from the cell via NCX and Ca2+-ATPase
Ca2+ stores are re-filled (by recycling cytosolic Ca2+, the SR is refilled using mitochondrial Ca2+ via the STORE-OPERATED CALCIUM CHANNEl - SOC channel)

Question 9

What are the ways in which calcium concentrations can rise in the cell?

Answer 9

Altered membrane permeability
Calcium released from rapidly-releasable stores
Calcium released from non rapidly-releasable stores

Question 10

How does altered membrane permeability result in an influx of calcium?

Answer 10

Voltage gated calcium channels can open in response to depolarisation
Receptor operated calcium channels can open in response to ligand binding

Question 11

How is calcium released from rapidly-releasable stores?

Answer 11

Calcium is stored in the SR by the SERCA protein
Inside the SR calcium binds to proteins such as CALSEQUESTRIN

G-protein coupled receptors:
A ligand binds to the gpcr on the membrane. The membrane binds to the membrane phopholipid PIP releasing IP3 which binds to a receptor on the SR, triggering release of calcium.

Calcium induced calcium release
Ca2+ binds to the RYANODINE receptor on the SR, triggering release of calcium.
e.g. CICR is important in cardiac myocytes

Question 12

Give an example of a non rapidly-releasable calcium store?

Answer 12

Calcium is taken into mitochondria when calcium concs are high as a protective mechanism