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M2M Exam 3 wk 2 > Ion channels > Flashcards

Ion channels Flashcards

1
Q

Ion Channels:

A

Membrane Proteins that open and close (“gate”).

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2
Q

When ion channels are open, they

A

only allow certain substances to pass (“selectivity”)

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3
Q

Ion channels are present

A

both in the plasma membrane and in membranes of intracellular organelles.

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4
Q

Their gating is controlled by a vast array of stimuli including:

A

temperature (hot/cold)
mechanical deformation
membrane potential
extracellular agents (taste, olfaction, neurotransmitters) intracellular agents (ATP, cAMP, Ca2+)

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5
Q

Some channels respond to multiple stimuli

A

e.g., both hot and capsaicin, voltage and Ca2+)

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6
Q

Gating stimulus:

A

ACh receptors, GABAA receptors.

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7
Q

Selectivity

A

Na+ channels, K+ channels, aquaporins

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8
Q

Muscle

A

contraction/relaxation, cardiac pacemaking

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9
Q

Neurons

A

sensory transduction, signal propagation, neurotransmitter release, postsynaptic responses, plasticity

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10
Q

T lymphocytes

A

activation

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11
Q

Pancreatic β cells

A

insulin release

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12
Q

Ion channels are important therapeutic targets

A

pain, arrhythmia, hypertension, epilepsy

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13
Q

conus geographus

A

a-conotoxin GVIA

Ca2+ channels

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14
Q

Sea krait

A

a-bungarotoxin

nicotinic AChRs

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15
Q

Ryania speciosa

A

ryanodine RyRs

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16
Q

Fugu

A

puffer fish
tetrodotoxin
Na+ channels

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17
Q

KV, NaV and CaV

A

4 membrane-spanning domains
Kv separate polypeptides
NaV, CaV linked together as 4 repeats (I, II, III, and IV)

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18
Q

KV, NaV and CaV

each of 4 domains

A

Each of the 4 domains contains 6 α-helices (S1-S6)

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19
Q

how do Kv Nav Cav sense voltage

A

S4 helices have positively charged residues (Lys/arg) at every third position and are the structures that sense voltage

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20
Q

s4 helices have

A

have positively charged residues (lys or arg) at

every third position and are the structures that “sense” voltage.

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21
Q

S5 and S6 helices, and the connecting “P loop”, assemble to form

A

the ion conducting pathway and “selectivity filter.”

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22
Q

selectivity filter

A

S5 and S6 helices and P loop form conduction pathway

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23
Q

Pentamer ligand-gated channels includes

A

(GABAAR, GlyR, nAChR, 5-HT3R)

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24
Q

Pentamer ligand-gated channels are:

A
  1. Heteropentamers. 4 transmembrane α-helices (M1-M4) per subunit.
  2. M2 helices surround a central, ion-conducting pathway.
  3. Selective for Cl- or cations with slight preference for Na+ over K+.
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25
Q

Tetrameric ligand gated channels. examples

A

Ionotropic glutamate receptors

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26
Q

Tetrameric ligand gated channels are:

A
  1. 4 subunits w/ 3 a-helices each

2. In NMDA receptors, two subunits bind glutamate, two bind glycine.

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27
Q

CLC chloride chanels

A
  1. Dimer
  2. Each subunit has an independently-gate pore
  3. Another gate controls both pores simultaneously
  4. Some ClC’s are H+/Cl- exchangers
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28
Q

aquaporins are

A
  1. tetramers
  2. each subunit contains a water pore
  3. water pores exclude al ions including H+
  4. in addition to water pores, a gated, central ion pore
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29
Q

Channel selectivity depends on

A
  1. size
  2. charge
  3. dehydration
  4. multiple binding sites
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30
Q

Selectivity varies examples

A

KV – K+:Na+ is 10,000:1;
CaV – Ca2+:Na+ is 3000:1; NaV – Na+:K+ is 12:1;
nAChR – Na+:K+ is 1.3:1

31
Q

Selectivity Size:

A

ions that are too large are rejected. However ionic crystal radius of Na+ < K+ yet rejected by KV

32
Q

Selectivity charge

A

Sign is important (cations vs anions). Valence also.

33
Q

Selectivity dehydration

A

Waters are removed and dehydrated ion interacts with protein environment within pore. Cannot bind too tightly (107 ions/sec per channel)

34
Q

Where are the activation and inactivation gates?

A
  1. S4 helices (4/channel) are the voltage sensors.
  2. The activation gate(s) likely represent the inner ends of the S6 helices swinging hinge-like motion around conserved glycines
35
Q

The inactivation gate of NaV channels is formed by ______

A

the cytoplasmic III-IV linker.

36
Q

Inactivation occurs when the

A

III-IV linker folds over the inner end of the ion-conducting pathway.

37
Q

Neurotransmitter receptors are either directly

A

ionotropic receptors

metabotropic receptor

38
Q

ionotropic receptors

A

coupled to ion channels (i.e. the receptor and channel are part of the same protein),

39
Q

metabotropic

A

activate second messenger pathways which can affect physically separate ion channels.

40
Q

A given neurotransmitter typically is able to activate both

A

ionotropic and metabotropic receptors.

41
Q

Within the ionotropic category are the

A

pentameric ligand gated channels,
also called the Cys-loop family of neurotransmitter receptor channels,
including the GABAARs, GlyRs, nAChRs and 5-HT3Rs

42
Q

Ions are energetically stabilized in solution by .

A

waters of hydration, which make the ions effectively larger in size

43
Q

Multiple binding sites can increase

A

selectivity

44
Q

If an ion interacts with multiple sites while traversing the channel pore, even relatively slight differences in the strength of interaction between

A

preferred and non-preferred ions at each site can result in a significant enhancement of overall selectivity for the preferred ion.

45
Q

Furthermore, the waters of hydration essentially mask

A

small differences in the size of the ions.

46
Q

Thus, ions must be substantially ______ before they pass through the channel pore,

A

de-hydrated

47
Q

To compensate for this dehydration, which is energetically ______, the ion is stabilized within the pore by _______

A

unfavorable

energetic interactions with the amino acids forming the pore (but not too much, or the ion would stay “stuck” in the pore).

48
Q

The energetic interactions of the ion with the pore can occur with

A

amino acid side chains (positive/basic residues: lysine or arginine; negative/acidic residues glutamate or aspartate),

with backbone carbonyls (negative) or

alpha helix dipoles (N-terminal: positive; C-teminal: negative).

These and other interactions depend on the sign, valence and size of the ion.

49
Q

“activation gate”, which can

A

rotate around a center pivot point. This rotation is controlled by a “voltage-sensing” charge, indicated by the “+” sign on the activation gate.

50
Q

When the inside of the cell is made negative the gate rotates ______ position and the current _____.

A

back to the closed

decays away

51
Q

The gating of NaV channels is more complicated because they have both

A

an activation gate and an inactivation gate.

52
Q

When the inside of the cell has a negative potential with respect to the outside, the gate is held in its _____ position and the current is ____.

A

closed

zero

53
Q

When the inside is made positive, the gate rotates to its ____ position and K+ ions flow ______.

A

open

out of the cell (upward deflection in the current)

54
Q

activation

A

when gate is open and K+ ions flow out of the cell and the current increases

55
Q

deactivation

A

the inside of the cell is made negative the gate rotates back to closed position and the current decays away.

56
Q

NaV activation gate, At negative potentials it is

A

closed and making the inside of the cell positive causes the NaV activation gate to swing open (“activate”) and sodium ions to flow into the cell (INa)

57
Q

The second NaV gate is the

A

the inactivation gate, is open at the resting potential because the activation gate occludes access to a site within the inner end of the pore at which the inactivation gate can bind.

58
Q

However, after the activation gate opens, the inactivation gate _____, a process called “____,” causing the current to _______.

A

closes

inactivation

decay to zero during a maintained depolarization

59
Q

Note that inactivation is not the same process as _____.

A

deactivation

60
Q

Also, the reversal of inactivation is called

A

“removal of inactivation.

61
Q

Selectivity occurs within a

A

central, ion conducting pathway formed by the four KV subunits or four repeats of NaV, where this central pathway is surrounded by S5 and S6 helices and connecting P loop contributed by the each of the four subunits or repeats (see above for the structures of NaV and KV).

62
Q

Voltage sensing is accomplished

A

by the S4 helices. These helices contain positively-charged Lys or Arg residues at every third position and translocate in response to changes in voltage across the membrane.

63
Q

when the activation gates are closed, they

A

occlude access to an enlarged space (“vestibule”) through which the ions pass before/after transiting a narrower constriction (the “selectivity filter” nearer to the extracellular side.

64
Q

The inactivation gate of NaV channels is formed by the: ________, When this cytoplasmic III-IV linker folds over the inner end of the central ion-conducting pathway, the channels is in a ______ state.

A

cytoplasmic loop which connects repeats III and IV

closed/inactivated

65
Q

The location of the selectivity filter is near the _____

A

the extracellular side,

66
Q

tetrodoxin (TTX) is a charged molecule that

A

cannot cross the membrane.

67
Q

When TTX is added to the extracellular side, it:

A

binds within the entrance of the pore, just above the selectivity filter of NaV

68
Q

The binding of TTX is

A

independent of the position of the activation/inactivation gates; TTX has no effect when added intracellularly.

69
Q

Lidocaine is a

A

tertiary amine and equilibrates between de-protonated (neutral) and protonated (positively charged) forms.

70
Q

The protonated form of lidocaine is dominant at

A

physiological pH and cannot cross the membrane, whereas the de-protonated form can.

71
Q

Protonated lidocaine has no effect on NaV from the ______ side but can block the channel from the

A

extracellular

intracellular side (thereby producing local anesthesia).

72
Q

The lidocaine block from the intracellular side can only occur if ______, which requires that the ______

A

the protonated lidocaine can access the vestibule

activation gate be open and that the inactivation gate not be closed.

73
Q

the lidocaine block is

A

“state-dependent.”

74
Q

if lidocaine is at its binding site within the vestibule, it can be trapped there if the

A

activation or inactivation gates are closed.

M2M Exam 3 wk 2 (11 decks)

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