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Biomembranes > CaV Channels > Flashcards

CaV Channels Flashcards

- List the subunits that assemble to form a voltage-gated Ca channel - List the subtypes and corresponding properties of CaV channels - Explain the importance and mechanism by which phosphorylation and G proteins regulate the Ca current from a CaV channel - Describe the clinical importance of Ca channels and list the channelopathies that may result from inherited mutations in CaV genes

1
Q

Functions of Ca channels

A
  • regulate intracellular calcium concentration and contribute to calcium signalling
  • mediate calcium entry into cells in response to depolarisaiton
  • control AP generation and conduction
  • control sensory processes
  • control muscle contraction
  • control secretion of transmitters and hormones
  • control cell differentiation and gene expression
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2
Q

What is the ionic requirement for release

A
  • calcium influx = fast evoked transmitter release
  • chemical signal carried by calcium is important, not the electrical charge
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3
Q

Structure of Ca channel alpha subunits

A
  • Four repeat domains
  • 6 TM segments, membrane-associated loop between S5 and S6
  • Glutamic acid residues in P regions are important for determining selectivity for calcium ions
  • auxillary subunits
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4
Q

Subtypes of calcoum channels

A
  • some require large depolarisation to elicit opening (HVA) / L-type
  • others open at more negative potentials (LVA) / T-type
  • HVA display variable inactivation
  • LVA display rapid voltage dependent inactivation
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5
Q

L type calcium channel

A
  • HVA
  • Blocked CHPs
  • E-C coupling, hormone secretion, muscle contraction
  • most have all 5 subunits
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6
Q

N type calcium channel

A
  • HVA
  • Blocked w-CTx* GVIA
  • Neurotransmitter release
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7
Q

P type calcium channel

A
  • HVA
  • blocked w-Aga * IVA (spider)
  • Neurotransmitter release
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8
Q

Q type calcium channel

A
  • HVA
  • Blocked w-CTx* MVIIC
  • Neurotransmitter release
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9
Q

R type calcium channel

A
  • H/LVA
  • Blocked SNX-482 (tarantula toxin)
  • Ca-APs and neurotransmitter release
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10
Q

T type calcium channel

A
  • LVA
  • Blocked Mibefradil
  • repetitive firing
  • structure unknown
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11
Q

Molecular basis of calcium channel diversity

A

diversity of Ca channels arises from the combination of five subunits

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12
Q

alpha1 subunit

A
  • has basic Na channel alpha subunit structure
  • 10 individual genes of these
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13
Q

beta subunit

A
  • 4 genes intracellularly located
  • each alpha subunit is associated with multiple beta subunits
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14
Q

alpha2 subunit

A
  • highly glycosylated
  • extracellularly locatedd
  • attached to membrane through disulphide linkage to delta subunit
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15
Q

delta subunit

A

anchors alpha2 complex to the alpha1 subunit via a single transmembrane segment

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16
Q

alpha2delta complex

A

occurs as 4 seperate genes

17
Q

gamma subunit

A
  • glycoprotein
  • 4 transmembrane segments
  • may be up to 8 genes involved
18
Q

Location of Cav1.1-4

A
  • L type
  • cardiac and skeletal muscle, neurons, and endocrine cells
19
Q

Location of Cav2.1

A
  • P/Q type
  • nerve terminals, dendrites
20
Q

Location of Cav2.2

A
  • N type
  • nerve terminals, dendrites
21
Q

Location of Cav2.3

A
  • R type
  • Cell bodies, nerve terminals, dendrites
22
Q

Location of Cav3.1-3

A
  • T type
  • cardiac and smooth muscle, neurons
23
Q

Describe the ‘mode-switching’ of L-type channels

A
  • multiple gating kinetics
  • during series of consecutive sweeps of depolarising pulses, see clusters of sweeps in 3 different kinetic modes
  • Mode1 = normal short open times
  • Mode0 - no openings
  • Mode2 = long open times
24
Q

Function of Beta-adrenergic agonists

A
  • increase cardiac AP amplitude, and muscle contractility and rate
  • mimicked by increase of cAMP in cell
  • PKA phosphorylates native beta subunits in cardiac tissue
  • other protein kinases activated by hormones/transmitters likely modulate Ca channel activity
25
Q

G-protein regulation of Cav2 family

A
  • inhibits calcium current
  • responsible for decrease in synaptic transmission as calcium entry at nerve terminal is reduced
  • GBY dimer mimics agonist actions (tonic inhibition of calcium current)
  • depolarisation reduces inhibitory effect
26
Q

What are the major classes of drugs that act on L-type Ca channels

A
  • Dihydropyridines (DHPs)
  • Phenylalkylamines
  • Benzothiazepines
  • used therapeutically to treat hypertension, cardiac arrhythmias and ischemic heart disease
27
Q

MoA of L-type Ca channel drugs

A
  • block calcium influx by more than one mechanism
  • dihydropyridines act as allosteric modulators, alter gating behaviour of L-type calcium channels
  • DHP antagonists stabilise Mode0 behaviour
  • DHP agonists increase Ca current by stabilising Mode2 behaviour
28
Q

How do DHPs block L-type calcium channels

A

bind to specific sites within S5 and S6 segments of alpha subunit

29
Q

How do Phenylalkylamines block L-type calcium channels

A
  • use-dependent manner from intracellular side of membrane via open channel block
  • bind to inner end of transmembrane pore (sites in S6 in domains III and IV)
30
Q

How do benzothiazepines block L-type calcium channels

A

bind to residues in S5-S6 linker of domain IV

31
Q

What is hypokalemic periodic paralysis type I caused by

A

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

32
Q

What is Timothy Syndrome caused by

A
  • rare childhood multi-organ disorder - cardiac defects, immune deficiency, cognitive abnormalities, generally sporadic
  • mutations in Cav1.2 cause loss of channel inactivation -> enhanced calcium entry -> severe cardiac dysregulation
33
Q

What is night blindess caused by

A
  • one form caused by decreased transmitter release from retinal photoreceptor terminals
  • mutiple mutations associated with loss of function of Cav1.4
34
Q

What is a migraine caused by

A
  • mutations of the Cav2.1 gene causing increased channel activity and transmitter release
35
Q

What is Episodic Ataxia Type II caused by

A
  • recurrent attacks of motor dysfunction
  • disruption of Cav2.1 gene
  • preventing formation of normal functional channels
  • loss of calcium current
36
Q

What is epilepsy caused by

A
  • mutations in calcium channel auxillary subunits
  • alter P/Q channel function
37
Q

What is autism spectrum disorder caused by

A

mutations in Cav3.2 (T-type), reduce channel activity

Biomembranes (12 decks)

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