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CaV channels Flashcards

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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
what blocks N type channels
conotoxin and GVIA
26
what is the function of N type channels
neurotransmitter release
27
what blocks P type channels
agatoxin and IVA
28
what is the function of P type channels
neurotransmitter release
29
what blocks Q type channels
conotoxin and MVCII
30
what is the function of Q type channels
neurotransmitter release
31
what blocks R type channels
tarantula toxin
32
what is the function of R type channels
Ca APs neurotransmitter release
33
what blocks T type channels
mibefradil
34
what is the function of T type channels
repetitive firing
35
how many auxhillary subunits do CaV channels arise from
5
36
how many individual genes does the alpha subunit have
10
37
how many beta subunits are there and where are they located
4 - intracellulary
38
how is the alpha 2 subunit attached to the membrane
through disulphide linkeage to a delta subunit, which anchors the alpha 1 subunit via a single transmembrane segment
39
what does the alpha2delta subunit occur as
4 seperate genes
40
what is the gamma subunit comprised of
a glycoproein with 4 transmembrane segments - and up to 8 genes
41
how many subunits do L type channels have
all 5
42
L type channels - location and channel type
CaV1.1-1.4 - cardiac and skeletal muscle, neurones and endocrine cells
43
P/Q type channels - location and channel type
CaV 2.1 - nerve terminals, dendrites
44
N type channels - location and channel type
CaV2.2 - nerve terminals, dendrites
45
R type channels - location and channel type
CaV2.3 - cell bodies, nerve terminals and dendrites
46
T type channels - location and channel type
CaV 3.1-3.3 - cardiac and smooth muscle, neurones
47
what do L-type CaV channels displau
multiple gating kinetics
48
what regulates the CaV1 family
phosphorylation
49
what are L-type CaV channels modulated by
hormones and neurotransmitters in muscle and neurones
50
what do B-adrenergic agonists increase
cardiac AP amplitude, muscle contractility and rate
51
what does adrenergic stimulation do
increase probability of opening and the number of functional CaV channels any process that causes increase in cAMP levels induces this effect
52
what does presence of a B-sunubit do
considerably enhance b-adrenergic agonist activation of CaV1.2
53
where does PKA phosphorylate native b subunits
cardiac tissue
54
what is the CaV2 family regulated by
G-proteins
55
what do GPCRs couple to
CaV channels - N, P/Q
56
what does g-protein coupling do
inhibits calcium current - local membrane action
57
what are g-proteins responsible for
a decrease in synaptic transmission as calcium entry at nerve terminal is reduced
58
what does a depolarizing prepulse within GPCRs do
reduces/abolishes the inhibitory effect
59
what regulates CaV channel activity
integration of multiple signalling pathways
60
what happens when CaV1.1 is missing/non-functional
die at birth of asphyxiation
61
what happens when CaV1.2 is missing/non-functional
die before birth as unable to contract cardiac muscle
62
what happens when CaV1.3 is missing/non-functional
deaf, cardiac arrhythmias
63
what happens when CaV1.4 is missing/non-functional
blind
64
what happens when CaV2.1 is missing/non-functional
severly ataxic, absence seizures
65
what happens when CaV2.2 is missing/non-functional
hyposensitivity to pain
66
what happens when CaV2.3 is missing/non-functional
hyposensitivity to pain
67
what happens when CaV3.1 is missing/non-functional
resistant to baclofen-induced seizures
68
what happens when CaV3.2 is missing/non-functional
resistant to baclofen-induced seizures
69
what happens when CaV3.3 is missing/non-functional
compromised vascular function
70
the major classes of drugs that act on L-type CaV channels are:
- DHPs -phenylalkylamines -benzothiazepines
71
what are drugs that act on L-type CaV channels used to treat
hypertension, cardiac arrhythmias and ischaemic heart disease
72
how do the drugs that work on L-type CaV channels work
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
what do dihydropyridines act as
allosteric modulators, in that they alter the gating behaviours of L-type CaV channels
74
where do DHPs bind
specific sites associated with the S5 and S6 segments of the alpha subunit
75
how do phenylalkylamines work
they block L-type Ca2+ channels in a use-dependant manner from the intracellular side of the membrane
76
where do PAAs bind
inner end of the transmembrane pore
77
where do benzothiapines bind/work
bind to residues in S5-S6 linker of domain IV, act extracellularlu
78
where are N, P/Q and R types exclusively associated with
the peripheral NS
79
where are T type channels exclusively associated with
cardiovascular and neuronal tissues
80
what is ziconotide and what does it do
a peptide toxin that interacts with N-type calcium channels
81
what is gabapentin and what does it do
originally synthesised as GABA - mimetics (for treatment of epilepsy) - used to treat chronic pain through their interaction at the alpha2delta subunit (supresses pain)
82
what is hypokalemic periodic paralysis (type 1)
CaV1.1 expressed specifically in skeletal muscle: mutations (S4 regions) result in reduced calcium current and muscle weakness
83
what is timothy syndrome
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
what is night blindness
multiple mutations (>60) associated with loss of CaV1.4 cause by decreased transmitter released from retinal photoreceptor terminals
85
what are migraines
a rare hereditary disorder resulting in transient migraine attacks associated with mutations of CaV2.1 causing increased channel activity and transmitter release
86
what is ataxia
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
what is epilepsy
mutations in CaV auxhillary subunits (alter P/Q function)

biomembranes (9 decks)

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