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Advanced Topics in Neuroscience 2 > Chloride channels, transporters, and disease > Flashcards

Chloride channels, transporters, and disease Flashcards

1
Q

What do chloride ions do ?

A

involved in body fluid and cellular homeostasis
- electrolyte balance
- acid/base balance
- secretion
- cell volume regulation
they are important for many physiological functions
inhibitory synaptic transmission such as ligand gated glycine and gaba a receptor

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2
Q

What do inherited defects in chloride channel genes cause?

A

they cause human disease

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3
Q

Which proteins form chloride channels ?

A

they are made of up from multiple unrelated families- convergent evolution
- they are not like potassium channels that have evolved from 1 channel, chloride channels are varied

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4
Q

What are examples of ligand gated chloride channels ?

A

GABA a receptor
glycine recepotor
form inhibitory synapse

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5
Q

What are examples of intracellular chloride channels ?

A

CLC family = CLC3-7

-maintain pH and ionic content or organeles- endosomes/lysosomes

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6
Q

What are examples of voltage gated chloride channels ?

A

CLC family=1,2 Ka and Kb

  • epithelial chloride transport
  • membrane excitability
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7
Q

What are examples of calcium activated Cl- channels ?

A

bestrophin, tweety (TTYH1-4) TMEM16A and some calcium activated chloride channels

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8
Q

What are examples of ATP-binding cassette (ABC) transporter protein ?

A

CTFR, P-glycoprotein

- CFTR is the only member that forms an ion channel

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9
Q

What are the members of the CLC family ?

A

9 members
- 1-7 plus Ka and Kb - encoded by CLCN1-7 genes and CLCNKA and CLCNKB
- have 18 transmembrane alpha helices with some just dipping in and out
- Ka and Kb are kidney specific - suppose to be
they are largely pH sensitive and they have a wide range of properties

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10
Q

What functional studies of CLC channels have been carried out ?

A

CLC-0 of torpedo electrolyte

CLC-1= mammalian skeletal muscle

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11
Q

What structural studies of CLC channels have been done?

A

from bacteria and algae

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12
Q

What are the plasma membrane ClC- channels from the CLC family ?

A

CLC-1, 2, Ka and Kb

- ka and kb have a beta-subinit which act as an accessory protein

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13
Q

What are the vesicular cl-/H+ exchangers from the CLC family ?

A

CLC-3,4, 5, 6,7

the chloride ions and protons move in the opposite direction

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14
Q

Why are KO mouse models of CLC members made?

A

because many of these channels are linked to human diseases and therefore KO of the gene in mice is used to mimic disorders

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15
Q

What do CLC cl- currents look like ?

A

flicker between open and closed states

- look like they have a double barrelled pore

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16
Q

What are the differences between Kv channels and CLC channels ?

A

CLCs have 2 subunits while Kv channels have 4 subunits

Kv channels have a single ion conducting pore in the centre whereas CLC channels have 2 pores

in most channels like Kv the channels are modular in structure and have distinct structural domain such as pore domains, voltage sensor, inactivation gate, ligand binding domain
BUT
pore and activation domains are not as distinct in CLCs and are poorly understood

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17
Q

What currents are recorded from patch clamp experiments?

A

HEK293 cells transfected with either CLC-5 or human BKca demonstrated macroscopic CL- currents

  • negative holding potential (-30 or -80mV) depolarising voltage pulses were applied
  • larger the depolarisation the large the outward current recorded
  • both give time dependent and outwardly rectifying macroscopic currents
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18
Q

What does outwardly rectifying current mean ?

A

there is more outward current than inward current
- outwad currents are carried by positively charged ions following out of the cell or negatively charged ions flowing into the cell
BKca and CLC-5 channels are pretty silent at negative potentials but as it depolarised the current increases

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19
Q

What are inwardly rectifying currents like ?

A

ion movement is opposite to outwardly rectifyfing current
so
positively charged ions flow into the cell or negatively charged ions flow out of the cell

20
Q

What is a non-rectifying current-voltgae relationship?

A

it is independent of voltage, voltage doesn’t affect its activity

21
Q

What are some examples of outwardly rectifying potassium channels ?

A

Kv - 6TMD and charged S4

BKca- 7TMD and charged S4

22
Q

What are some examples of outwardly rectifying chloride channels ?

A

CLC-1, 3-7

23
Q

What are some examples of inwardly rectifying chloride channels ?

A

CLC-2

24
Q

What are some examples of inwardly rectifying potassium channels ?

A

Kir - 2TMD, intracellular block by magnesium and polyamines

25
Q

What are some examples of voltage-independent potassium channels?

A

K2P- 4TMD, dimers

SKCa/IKCa- 6TMD, no charged S4

26
Q

What are some examples of voltage-independent chloride channels?

A

CLC-Ka, Kb - weak voltage dependence if any - dont have voltage sensors

27
Q

Where are ABC transporters present and what drives them ?

A

seem to be present in all different cellular life forms- very old group of proteins
ATP hydrolysis drives transport of substances out of cells- hormones, steroid, bile, lipids and cholesterol
- moving hydrophobic substances across the membrane

28
Q

What are the subfamilies of ABC transporter family ?

A

A-F

29
Q

What is the ABC component made up of ?

A

pair of nucleotide binding domains, each with walker A and B motifs

30
Q

What is ABCC1?

A

multi drug resistance-associated protein 1 (MRP1)

31
Q

What is ABCC7?

A

cystic fibrosis transmembrane conductance regulator - acts as an ion channel not a transporter

32
Q

What are ABCC8 and 9?

A

sulphonylurea receptors SUR1 and SUR2

- dont seem to transport anything, act like accessory proteins

33
Q

What is a simplified model of ion channel kinetics?

A

3 state model with 2 closed states and 1 open state

the 2 closed states are C1 and C2 and C2 is the state that is more likely to open

34
Q

Once the channel is open what determines the size and direction of the current ?

A

single channel conductance and the ion driving force determine the size and direction of the current

35
Q

What type of ions dont affect how much the channels open and close?

A

substrate ions dont affect how the channels open and close

36
Q

What is meant by markovian kinetics ?

A

transitions between states are stochastic processes
i.e. probability that they will occur and are not affected by the previous state - no memory and no specific order in which transitions occur

37
Q

What is the transporter (enzyme) kinetics?

A

look up diagram

38
Q

What are the kinetics of transporters dependent upon ?

A

dependent upon interactions between substrate and enzyme (michaelis-menten)

the ions are transported during transitions between states
its cyclical
the source of ATP ensures it is always going in a clockwise direction

39
Q

What does the post-albers transport cycle of the sodium/potassium pump form ?

A

it forms a channel with 2 gates, never simultaneously open

- only 1 gate can be open at any one time as if they were both open at the same time then it would form an ion channel

40
Q

When was CFTR identified?

A

identified as the faulty gene in cystic fibrosis

it is a member of the ABC transporter family but is a cl- channel

41
Q

How is CFTR gated?

A

gated by cytoplasmic ATP and stimulated by cAMP

42
Q

What does channel opening and closing of CFTR require?

A

requires ATP hydrolysis by the NBDs

each cycle where ATP is hydrolysed about 10 to the power of 6 cl- ions pass through the channel

43
Q

What is CFTR referred to as?

A

a broken transporter that leaks cl-

44
Q

What residue is important in cystic fibrosis?

A

phenylalanine 528

it has 2 6TMD segments but is a single peptide chain

45
Q

What are CFTR kinetics like ?

A

follow transporter kinetic scheme
transition between different states including when the pore is closed
- requires 2 tap to bind to enable the channel to open

46
Q

What transporter like behaviours are seen in the CLC Cl- channels ?

A
  • asymmetric non-markovian gating dependence on H+ gradient- this supplies the energy
  • tiny bit of H+ transported through CLC-1
  • are CLC Cl- channels broken/leaky transporters
    proton gradient drives transport like cyclical behaviour - clockwise manner

Advanced Topics in Neuroscience 2 (17 decks)

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