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Jacopo Biomembranes > Lecture 17 > Flashcards

Lecture 17 Flashcards

1
Q

What is the function of voltage gated calcium channels?

A

They help regulate intracellular calcium concentration and contribute to calcium signaling. They mediate Ca2+ entry into the cell in response to depolarisation.

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2
Q

What are the cellular events that voltage gate calcium channels control?

A 
AP generation and conduction
Sensory processes
Muscle contraction
Secretion of transmitters and hormones
Cell differentiation and gene expression
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3
Q

What modulates the opening of calcium channels?

A

1) Hormones
2) Transmitters
3) Protein kinases
4) Protein phosphatases

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4
Q

What is spontaneous mutation of Ca2+ channel subunits associated with?

A

Hyperexcitable disorders.

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5
Q

What does calcium influx triggers?

A

Fast evoked transmitter release. An elevation in intracellular calcium is an absolute requirement for transmitter release. Na+ and K+ ions are not necessary for release.

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6
Q

What are the intra and extracellular concentration of calcium at rest?

A

1-2 mM outside

<0.1mM inside

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7
Q

What is the difference between Ca2+ and other ions?

A

That unlike otherions (Na+, K+, Cl-) is the CHEMICAL signal carried by Ca2+ that is important and not the electrical charge of the ion.

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8
Q

How is the primary structure of Ca2+ channels?

A

It is similar to the subunit of Na+ channel. Four repeat domains, each with six transmembrane segments and a membrane associated loop between S5 and S6. Glutamic acid residue (E) in the P regions of each domain are important for determining selectivity for calcium ions (DEKA in sodium channel). Like Na+ there are auxillary subunits.

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9
Q

What are the two main types of Calcium channels based on the voltage required to activate them?

A

1) High-voltage activated (HVA): require a large depolarisation (e.g -20mV) to elicit opening.
2) Low-Voltage activated (LVA): require a more negative potentials (-60 mV) to open.

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10
Q

Describe inactivation of HVA Ca2+ channels:

A

They display variable inactivation, some hardly inactivate over a 200 ms depolarising pulse, others completely inactivate at this time.

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11
Q

Describe inactivation of LVA Ca2+ channels:

A

Generally display rapid voltage inactivation, like that observed for Na+ channels.

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12
Q

How are HVA also classified?

A

Since they are long-lasting they are called L-type calcium channels.

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13
Q

How are LVA also classified?

A

They display voltage-dependent inactivation and are termed Transiet or T-type calcium channels.

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14
Q

What are the 6 types of calcium channels?

A 
L (Long-Lasting)
T (Transient)
N (neuronal)
P (Purkinje cell)
Q (Cerebellar granule neurones)
R (Resistant compoent of neuronal current)
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15
Q

Where are the different types of calcium channels usually found?

A

L and T are found in a wide range of cells, N, P, Q and R are mostly found in neurons.

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16
Q

Describe L-type calcium channels:

A

HVA

E-C coupling, Hormone secn, muscle contraction

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17
Q

Describe T-type calcium channels:

A

LVA
Repetitive firing
If absent patient die before birth as unable to contract

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18
Q

Describe N-type calcium channels:

A

HVA

Neurotransmitter release

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19
Q

Describe P-type and Q-type calcium channels:

A

HVA

NT release

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20
Q

What did molecular and cloning studies revealed?

A

That diversity of Ca2+ channels arises from the combination of five subunits.

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21
Q

Describe R-type calcium channels:

A

H/LVA
Ca-action potentials
NT release

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22
Q

Describe α1 subunit of calcium channels:

A

The α1 subunit has the basic Na+ channel α subunit structure and there appear to be 10 (individual genes) of these.

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23
Q

Describe α2 subunit of calcium channels:

A

The α2 subunit, extracellularly located, is attached to the membrane through disulfide linkage to a δ subunit which anchors the complex to the α1 subunit via a single transmembrane segment.

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24
Q

Describe β subunit of calcium channels:

A

There is a β subunit (4 separate genes identified) which is intracellularly located. Each α subunit is associated with multiple β subunits.

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25
Q

Describe the α2δ subunit of calcium channels:

A

It occurs as 4 separate gees, a single gene encodes α2 and δ subunits.

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26
Q

Describe the γ subunit of calcium channels:

A

A glycoprotein with four transmembrane segments, may be up to 8 genes but involvement is not entirely clear.

27
Q

Describe CaV1.1-4:

A

Current type: L

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

28
Q

Describe CaV2.1:

A

Current Type: P/Q

Location: nerve terminal, dendrites.

29
Q

Describe CaV2.2:

A

Current type: N

Location: Nerve terminal, dendrites

30
Q

Describe CaV2.3:

A

Current type: R

Location: Cell bodies, nerve terminals, dendrites.

31
Q

Describe CaV 3.1-3:

A

Current type: t

Location: Cardiac and smooth muscle, neurons.

32
Q

What have single channel recordings demonstrated?

A

That L-type Ca2+ channels display multiple gating kinetics and during series of consecutive sweeps of depolarising pulses, see clusters of sweeps in thtick modes.

33
Q

What are the three different kinetics modes?

A

Mode 1: normal short open time
Mode 0: No openinigs
Mode 2: long open times

34
Q

How are L-type Ca2+ channels modulated?

A

Modulated by hormones and neurotransmitters in muscle (skeletal, smooth and cardiac) and neurons. A good example is the enhancement of Ca2+ current in the heart by catecholamines, which underlies their positive ionotropic action.

35
Q

What do β-adrenergic agonists do?

A

β-adrenergic agonists increase cardiac potential amplitude, and muscle contractility and rate.

36
Q

What is the result of adrenergic stimulation?

A

Single channels recording show 2 actions of β1-adrenergic stimulation. This stimulation increase probability of opening (more mode 2 behavior) and the apparent number of functional Ca2+ channels. This action can be mimicked by increase in cAMP

37
Q

What does protein kinase A (PKA) do?

A

cAMP-dependent protein kinase A (PKA) phosphorylates a subunit on serine 1928 of CaV1.2 to mediate an increase in Ca2+ current. However, this increase is much less than observed for native channels.
PKA phosphorylates native β-subunit in cardiac tissue.

38
Q

What does the presence of β-subunit enhance?

A

It considerably enhances b-adrenergi agonist activation of CaV1.2 (by phosphorylation of serine 478/479).

39
Q

What do GPCRs do in CaV2 family?

A

GPCRs couple to CaV channels- N, P, Q (e.g α2 adrenoreceptors, μ and δ opioid receptors, GABAb, Adenosine A1 receptors). This coupling inhibits calcium-current (local membrane action) and is responsible for a decrease in synaptic trasmission as calcium entry at nerve terminal is reduced.

40
Q

What is the common feature of GPCRs coupling and what does this imply?

A

Gβγ dimers mimics agonist actions (tonic inhibition of calcium current). Gβγ dimer in membrane patch was sufficent to inhibit calcium current, this imply that a depolarizing prepulse reduces/abolished the inhibitory effect. This means that integration of multiple signalling pathways regulates CaV activity.

41
Q

What happens if Ca1.1 is absent?

A

Patient die at birth of asphyxiation.

42
Q

What happens if Ca1.2 is absent?

A

Patient die before birth as unable to contract cardiac muscle.

43
Q

What happens if Ca1.3 is absent?

A

Patient is deaf and suffer cardiac arythmias.

44
Q

What happens if Ca1.4 is absent?

A

Patient is blind.

45
Q

What happens if Ca2.1 is absent?

A

Patient is severely ataxic, absence seizures.

46
Q

What happens if Ca2.2 is absent?

A

Patient suffer of hyposensitivity to pain.

47
Q

What happens if Ca2.3 is absent?

A

Patient suffer of hyposensitivity to pain and is resistant to baclofen-induced seizures.

48
Q

What happens if Ca3.2 is absent?

A

Patient suffer of compromised vascular function.

49
Q

What are the five major classes of drugs that act on L-Type Ca2+ channels?

A

1) Dihydropyridines (DHPs)
2) Phenylalkylamines
2) Benzothiazepines

50
Q

How do drugs that act on L-type Ca2+ channels function?

A

These drugs act to bloc Ca2+ influx and they do so by more than one mechanism, drugs may bind to the same site but have converse effects.

51
Q

How do DHP act?

A

Act as allosteric modulators, in that they alter the gating behavior of L-Type Ca2+ channels.

52
Q

How do DHP antagonist act?

A

They act to stabilize mode 0 behavior. Agonists are possible and BAYK8644 increases Ca2+ current by stabilizing mode 2 behavior.

53
Q

What did mutations studies reveal about the action of DHPs?

A

Mutation studies indicate that the DHPs bind to specific sites associated with S5 and S6 segments of the subunit (particulary III and IV domains) although there is a contribution from IS6 segment.

54
Q

How do phenylalkylamines perform their action on Calcium channels?

A

They block L-type Ca2+ channels in a use-dependent manner from the intracellular side of the membrane, similar to the action of LAs on Na+ channels (open channel block).

55
Q

Where do phenylalkylamines bind?

A

It is thought that they bind to the inner end of transmembrane pore (sites in S6 domains III and IV), some overlap with DHPs.

56
Q

What are two promising leads to cure Ca2+-related pain diseases?

A

Ziconotide: a peptide toxin that interacts with -type calcium channels (chronic neuropathic pain)
Gabapentin/pregabalin: originally synthesized as a GABA-mimetics (for treatment of epilepsy), used to treat chronic pain through their interaction at the α2δ subunit.

57
Q

Describe Hypokalemic periodic paralysis (type1):

A

Cav1.1 expressed specifically in skeletal muscle: mutations (S4 regions) result in reduced calcium current and muscle weakness

58
Q

Describe Timothy Syndrome:

A

a rare childhood multi-organ disorder - cardiac defects, immune deficiency, cognitive abnormalities etc. Generally sporadic. Due to mutations in Cav1.2 causing loss of channel inactivation and so enhanced calcium entry leading to severe cardiac dysregulation.​

59
Q

Describe night Blindness:

A

One form of this condition is caused by decreased transmitter released from retinal photoreceptor terminals. Multiple mutations (> 60) associated with loss of function of CaV1.4 (L-type calcium channel)​.

60
Q

Describe Migraine:

A

One form (Familial Hemiplegic Migraine - FHM) a rare hereditary disorder resulting in transient migraine attacks is associated with mutations of the CaV2.1 gene (P/Q channel a subunit) causing increased channel activity and transmitter release.​

61
Q

Describe Episodic Ataxia Type 2:

A

patients have recurrent attacks of motor (cerebellar) dysfunction. Also associated with disruption of CaV2.1 gene (>20 known mutations) preventing formation of normal functional channels and so loss of calcium current​.

62
Q

Describe Epilepsy:

A

Recently it has been suggested that mutations in Ca2+ channel auxiliary subunits may be associated with certain forms of epilepsy. The b4, g2 & a2delta subunits have mutations that alter P/Q channel function​.

63
Q

Desribe Autism spectrum disorder:

A

mutations in Cav3.2 (T-type) associated with this disorder (patients also suffer from epilepsy) - all reduce channel activity​

Jacopo Biomembranes (16 decks)

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