The Voltage-activated Calcium Channels Flashcards Preview

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Flashcards in The Voltage-activated Calcium Channels Deck (68)
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1
Q

What is the function of the voltage-activated calcium channels?

A

Regulate intracellular calcium conc. and contribute to calcium signalling.

2
Q

What do the voltage-activated calcium channels mediate?

A

Calcium entry into cells in response to depolarisation.,

3
Q

Name the 5 different cellular events that voltage-activated calcium channels control?

A
  1. AP generation and conduction.
  2. Sensory processes.
  3. Muscle contraction
  4. Secretion of transmitters and hormones.
  5. Cell differentiation and gene expression.
4
Q

Name the 4 different modulators of calcium channels?

A
  1. Hormones.
  2. Transmitters
  3. Protein kinases.
  4. Phosphatases.
5
Q

What is associated with spontaneous mutations of calcium channels?

A

Hyperexitable disorders.

6
Q

What is triggered by calcium influx?

A

Fast evoked transmitter release.

Elevation of intracellular calcium conc. is an absolute requirement for transmitter release.

7
Q

What signal is the important factor when calcium enters the cell?

A

The chemical signal.

The calcium itself is necessary not the charge that comes with it.

8
Q

How many domains does the calcium channel have?

A

4 repeat domains.

9
Q

How many transmembrane segments are in each domain?

A

6 transmembrane domains.

10
Q

Where is the membrane-associated loop in the calcium channel?

A

Between S5 and S6.

11
Q

What is the importance of the glutamic acid residue in the P regions of each domain?

A

Important in determining the selectivity for calcium ions.

12
Q

How are the calcium channels subdivided?

A

On the basis of the voltage-required to activate them.

13
Q

Name the 2 subtypes of calcium channels?

A
  1. High-voltage activated calcium channels (HVA)

2. Low-voltage activated calcium channels (LVA)

14
Q

What are the properties of the HVA calcium channels?

A

Require a large depolarisation (-20mV) to elicit opening.

Display variable inactivation

15
Q

What are the properties of the LVA calcium channels?

A

The calcium channels in this group open at a much more negative potential (-50mV)
Generally display rapid voltage dependent inactivation.

16
Q

What are the other names given to the HVA and LVA? and why is that?

A

HVA channels are also called L-type. They are long-lasting.

LVA channels are also called T-type (transient). They display fast voltage-dependent inactivation

17
Q

Name the 6 different subtypes of calcium channels?

A
  1. L-type; long-lasting
  2. T-type; transient
  3. N-type; neuronal.
  4. P-type; purkinje cell.
  5. Q-type; cerebellar granule neurones.
  6. R-type; resistant component.
18
Q

Where are the L- and T-type calcium channels found in the body?

A

In a wide range of cells.

19
Q

Where are the N-, P-, Q- and R-type calcium channels found in the body?

A

Mostly found in neurones.

20
Q

Describe the properties of the L-type calcium channel?

A

HVA.
Blocked by dihydropyridines
Important in hormone secretion.

21
Q

Describe the properties of the N-type calcium channel?

A

HVA.
Blocked by conotoxin
Important in the neurotransmitter release.

22
Q

Describe the properties of the P-type calcium channel?

A

HVA
Blocked of the agatoxin.
Important in the neurotransmitter release.

23
Q

Describe the properties of the Q-type calcium channel?

A

HVA
Blocked by conotoxin.
Important in neurotransmitter release.

24
Q

Describe the properties of the R-type calcium channel?

A

H/LVA
Blocked by tarantula toxin.
Important in the action potential process.

25
Q

Describe the properties of the T-type calcium channel?

A

LVA
Blocked by mibefradil.
Important in repetitive firing.

26
Q

What is the reason for the diversity of calcium channels?

A

Arises from the combination of five subunits.

27
Q

Describe the properties of the alpha 1 subunit of the calcium channel?

A

The basic sodium channel a subunit structure.

Appear to be 10 genes that code them.

28
Q

Describe the properties of the beta subunit of the calcium channel?

A

Intracellularly located.
4 genes that code them.
Each subunit is associated with multiple beta subunits.

29
Q

Describe the properties of the alpha 2 subunit of the calcium channel?

A

Extracellularly located.

Attached to the membrane through disulphide linkage to a delta subunit.

30
Q

Properties of the delta subunit of the calcium channel?

A

Linked with the alpha 2 subunit through disulphide linkage.

Anchors the complex to the alpha 1 subunit via single transmembrane segment.

31
Q

How many genes code for this alpha 2: delta subunit?

A

4 separate genes.

32
Q

Properties of the gamma subunit of the calcium channel?

A

A glycoprotein.
4 Transmembrane segments
Up to 8 genes involved.

33
Q

How many subunits does the L-type channel have?

A

All 5 subunits.

34
Q

Describe the properties of the calcium voltage dependent channel 1.1, 1.2, 1.3 and 1.4?

A

Current type: L

Location: cardiac, skeletal muscle, neurones and endocrine cells.

35
Q

Describe the properties of the calcium voltage dependent channel 2.1?

A

Current type: P/Q

Location: nerve terminals, dendrites

36
Q

Describe the properties of the calcium voltage dependent channel 2.2?

A

Current type: N

Location: nerve terminals, dendrites

37
Q

Describe the properties of the calcium voltage dependent channel 2.3?

A

Current type: R

Location: cell bodies, nerve terminals and dendrites

38
Q

Describe the properties of the calcium voltage dependent channel 3.1, 3.2 and 3.3?

A

Current type: T

Location: cardiac, smooth muscle and neurones.

39
Q

Name the 3 different modes that the L-type calcium channel can display?

A

Mode-switiching- multiple gating kinetics.

  1. MODE 1: normal short open times.
  2. MODE 0: no openings.
  3. MODE 2: long open times
40
Q

What modulates the L-type calcium channels?

A

By hormones and neurotransmitters in muscle and neurones.

41
Q

What does the beta-adrenergic agonist do?

A

Increase cardiac AP amplitude
Muscle contractility and rate.
Does this by shifting the gating of the L-type channel or by opening more calcium channels.

42
Q

What happens the adrenergic is stimulated?

A

Increase probability of opening the calcium channel.

Increases the apparent number of functional calcium channels.

43
Q

What mimics the adrenergic stimulation?

A

Increase of cAMP in the cell

44
Q

How does cAMP mediate an increase in calcium current?

A

cAMP-dependent protein kinase A (PKA) phosphorylates a subunit on the calcium 1.2 channel to increase the calcium current.

45
Q

When a beta-subunit is present what happens when b-adrenergic agonist is present?

A

Enhances the agonist activation of the calcium 1.2 channel.

46
Q

What is coupled to calcium channels N, P/Q?

A

GPCRs.

47
Q

The role the GPCRs play in the N, P/Q calcium channels function?

A

Inhibits calcium current- causes a decrease in synaptic transmission.

48
Q

Gby dimer role in the regulation of calcium 2 family by G-proteins?

A

Mimics agonist actions-tonic inhibition of calcium current.

49
Q

Name the 3 major classes of drugs that act on L-type calcium channels?

A
  1. Dihydropyridines.
  2. Phenylalkylamines.
  3. Benzothiazepines.
50
Q

Why are the drugs that affect L-type calcium channels clinically relevant?

A

Used therapeutically to treat hypertension, cardiac arrhythmias and ischaemic heart disease.

51
Q

How do the drugs act on the L-type calcium channel?

A

Act to block calcium influx.
DHP: act as allosteric modulators- alter the gating behaviour.
DHP antagonists: act to stabilise mode 0 behaviour.

52
Q

What does the agonist do to the mode of the L-type calcium channel?

A

Changes it from MODE1 to MODE2.

53
Q

What does the antagonist do to the mode of the L-type calcium channel?

A

Changes it from the MODE1 to MODE0

54
Q

Where does the DHPs bind to the calcium channel?

A

At the S5-6 segment on the alpha subunit

55
Q

Properties of the phyenylalkylamines?

A

Blocks L-type calcium channels in a use-dependent manner.

Blocks from the intracellular side.

56
Q

Properties of the benzothiazepines?

A

Act extracellularly.

Binding to residues in S5-6 of the 4th domain

57
Q

What tissue are N, P/Q and R type calcium channels associated with?

A

Peripheral and CNS

58
Q

What tissue is the T-type calcium channel associated with?

A

Cariovascular and neuronal tissues

59
Q

What medical conditions are associated with neuronal calcium channels?

A

Epilepsy and pain.

60
Q

Function of ziconotide?

A

Drug used to treat chronic neuropathic pain.

Peptide toxin that interacts with N-type calcium channel.

61
Q

Function of gabapentin/pregabalin?

A

Used to treat chronic pain through their interactions at the alpha 2 delta subunit.

62
Q

Describe hypokalemic periodic paralysis?

A

Calcium 1.1 channel mutation in the S4 regions cause a reduced calcium current and muscle weakness

63
Q

Describe timothy syndrome?

A

A rare childhood multi-organ disorder.
Mutations in the calcium 1.2 channel.
Loss of channel inactivation.

64
Q

Describe night blindness?

A

Loss of function of calcium 1.4 channel.

65
Q

Describe the cause of migraine?

A

Associated with mutations of the calcium 2.1 channel.

Causing increased channel activity and transmitter release.

66
Q

Describe the cause of ataxia type 2?

A

Disruption of the calcium 2.1 gene.

Loss of calcium current.

67
Q

Describe the cause of epilepsy?

A

Mutations in the calcium channel auxiliary subunits associated with certain forms of epilepsy.

68
Q

Describe the cause of the autism spectrum disorder?

A

Mutations in the calcium 3.2 channel.

Reduce channel activity