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biomembranes > CaV channels > Flashcards

CaV channels Flashcards

1
Q

what do CaV regulate

A

intracellular calcium concnetration and contribute to calcium signalling

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2
Q

what do CaV mediate

A

calcium entry into cells in response to depolarisation

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3
Q

what do CaV control

A
  • AP generation and conduction
  • sensory processes
  • muscle contraction
  • secretion of transmitters and hormones
  • cell differentiation and gene expression
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4
Q

what is the opening of CaV channels modulated by

A

hormones, transmitters, protein kinases and phosphatases

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5
Q

what are CaV targets for

A

toxins and drugs

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6
Q

what is spontaneous mutations of CaV channel subunits associated with

A

hyperexcitable disorders

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7
Q

what is the trigger for fast evoked transmitter release

A

calcium influx

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8
Q

what is the typical calcium concentrations at rest

A

extracellularly 1-2mM
intracellularly <0.1mM

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9
Q

what is required for transmitter release

A

an elevation in intracellular calcium concentration

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10
Q

what is the primary structure of the CaV subunit

A

4 repeat domains, each with 6 transmembrane segments and a membrane-associated loop between S5 and S6

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11
Q

what are present in the P regions of each domain that are important for determining selectivity for calcium ions

A

glutamic acid residues (E)

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12
Q

what do high-voltage activation calcium channels require

A

large depolarisation (to -20mV)

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13
Q

what do low-voltage activation calcium channels require

A

much more negative potentials (-60mV)

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14
Q

what do HVA calcium channels display

A

variable inactivation

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15
Q

what do LVA channels display

A

rapid voltage dependant inactivation

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16
Q

as HVA channels are long-lasting, they are also called

A

L-type calcium channels

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17
Q

as LVA channels display fast voltage-dependant inactivation, they are termed as

A

transient, or T-type calcium channels

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18
Q

what are N-type channels

A

neuronal (HVA)

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19
Q

what are P-type channels

A

purkinje cells (HVA)

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20
Q

what are Q-type channels

A

found in cerebellar granule neurones (HVA)

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21
Q

what are R type channels

A

so-called resistant component of neuronal channels (L/HVA)

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22
Q

where are the different channel types found

A

L and T are found in a wide range of cells
N, P, Q and R are typically found in neurones

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23
Q

what blocks L type channels

A

DHPs

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24
Q

what is the function of L type channels

A

E-C coupling
hormone secretion
muscle contraction

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25
Q

what blocks N type channels

A

conotoxin and GVIA

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26
Q

what is the function of N type channels

A

neurotransmitter release

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27
Q

what blocks P type channels

A

agatoxin and IVA

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28
Q

what is the function of P type channels

A

neurotransmitter release

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29
Q

what blocks Q type channels

A

conotoxin and MVCII

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30
Q

what is the function of Q type channels

A

neurotransmitter release

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31
Q

what blocks R type channels

A

tarantula toxin

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32
Q

what is the function of R type channels

A

Ca APs
neurotransmitter release

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33
Q

what blocks T type channels

A

mibefradil

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34
Q

what is the function of T type channels

A

repetitive firing

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35
Q

how many auxhillary subunits do CaV channels arise from

A

5

36
Q

how many individual genes does the alpha subunit have

A

10

37
Q

how many beta subunits are there and where are they located

A

4 - intracellulary

38
Q

how is the alpha 2 subunit attached to the membrane

A

through disulphide linkeage to a delta subunit, which anchors the alpha 1 subunit via a single transmembrane segment

39
Q

what does the alpha2delta subunit occur as

A

4 seperate genes

40
Q

what is the gamma subunit comprised of

A

a glycoproein with 4 transmembrane segments - and up to 8 genes

41
Q

how many subunits do L type channels have

A

all 5

42
Q

L type channels - location and channel type

A

CaV1.1-1.4 - cardiac and skeletal muscle, neurones and endocrine cells

43
Q

P/Q type channels - location and channel type

A

CaV 2.1 - nerve terminals, dendrites

44
Q

N type channels - location and channel type

A

CaV2.2 - nerve terminals, dendrites

45
Q

R type channels - location and channel type

A

CaV2.3 - cell bodies, nerve terminals and dendrites

46
Q

T type channels - location and channel type

A

CaV 3.1-3.3 - cardiac and smooth muscle, neurones

47
Q

what do L-type CaV channels displau

A

multiple gating kinetics

48
Q

what regulates the CaV1 family

A

phosphorylation

49
Q

what are L-type CaV channels modulated by

A

hormones and neurotransmitters in muscle and neurones

50
Q

what do B-adrenergic agonists increase

A

cardiac AP amplitude, muscle contractility and rate

51
Q

what does adrenergic stimulation do

A

increase probability of opening and the number of functional CaV channels
any process that causes increase in cAMP levels induces this effect

52
Q

what does presence of a B-sunubit do

A

considerably enhance b-adrenergic agonist activation of CaV1.2

53
Q

where does PKA phosphorylate native b subunits

A

cardiac tissue

54
Q

what is the CaV2 family regulated by

A

G-proteins

55
Q

what do GPCRs couple to

A

CaV channels - N, P/Q

56
Q

what does g-protein coupling do

A

inhibits calcium current - local membrane action

57
Q

what are g-proteins responsible for

A

a decrease in synaptic transmission as calcium entry at nerve terminal is reduced

58
Q

what does a depolarizing prepulse within GPCRs do

A

reduces/abolishes the inhibitory effect

59
Q

what regulates CaV channel activity

A

integration of multiple signalling pathways

60
Q

what happens when CaV1.1 is missing/non-functional

A

die at birth of asphyxiation

61
Q

what happens when CaV1.2 is missing/non-functional

A

die before birth as unable to contract cardiac muscle

62
Q

what happens when CaV1.3 is missing/non-functional

A

deaf, cardiac arrhythmias

63
Q

what happens when CaV1.4 is missing/non-functional

A

blind

64
Q

what happens when CaV2.1 is missing/non-functional

A

severly ataxic, absence seizures

65
Q

what happens when CaV2.2 is missing/non-functional

A

hyposensitivity to pain

66
Q

what happens when CaV2.3 is missing/non-functional

A

hyposensitivity to pain

67
Q

what happens when CaV3.1 is missing/non-functional

A

resistant to baclofen-induced seizures

68
Q

what happens when CaV3.2 is missing/non-functional

A

resistant to baclofen-induced seizures

69
Q

what happens when CaV3.3 is missing/non-functional

A

compromised vascular function

70
Q

the major classes of drugs that act on L-type CaV channels are:

A
  • DHPs
    -phenylalkylamines
    -benzothiazepines
71
Q

what are drugs that act on L-type CaV channels used to treat

A

hypertension, cardiac arrhythmias and ischaemic heart disease

72
Q

how do the drugs that work on L-type CaV channels work

A

act to block Ca2+ influx and they do so by more than 1 mechanisms, drugs may bind to the same site but have converse effects

73
Q

what do dihydropyridines act as

A

allosteric modulators, in that they alter the gating behaviours of L-type CaV channels

74
Q

where do DHPs bind

A

specific sites associated with the S5 and S6 segments of the alpha subunit

75
Q

how do phenylalkylamines work

A

they block L-type Ca2+ channels in a use-dependant manner from the intracellular side of the membrane

76
Q

where do PAAs bind

A

inner end of the transmembrane pore

77
Q

where do benzothiapines bind/work

A

bind to residues in S5-S6 linker of domain IV, act extracellularlu

78
Q

where are N, P/Q and R types exclusively associated with

A

the peripheral NS

79
Q

where are T type channels exclusively associated with

A

cardiovascular and neuronal tissues

80
Q

what is ziconotide and what does it do

A

a peptide toxin that interacts with N-type calcium channels

81
Q

what is gabapentin and what does it do

A

originally synthesised as GABA - mimetics (for treatment of epilepsy) - used to treat chronic pain through their interaction at the alpha2delta subunit (supresses pain)

82
Q

what is hypokalemic periodic paralysis (type 1)

A

CaV1.1 expressed specifically in skeletal muscle: mutations (S4 regions) result in reduced calcium current and muscle weakness

83
Q

what is 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 lack of channel inactivayion and so enchanced calcium entry leading to severe cardiac dysregulation

84
Q

what is night blindness

A

multiple mutations (>60) associated with loss of CaV1.4
cause by decreased transmitter released from retinal photoreceptor terminals

85
Q

what are migraines

A

a rare hereditary disorder resulting in transient migraine attacks
associated with mutations of CaV2.1 causing increased channel activity and transmitter release

86
Q

what is ataxia

A

patients have recurrent attacks of motor dysfuncion
associated with disruption of CaV2.1 gene, preventing formation of normal functional channels and so loss of calcium current

87
Q

what is epilepsy

A

mutations in CaV auxhillary subunits (alter P/Q function)

biomembranes (9 decks)

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