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Cell and molecular extras > Lecture 8 Ligand gated ion channels > Flashcards

Lecture 8 Ligand gated ion channels Flashcards

1
Q

Why do we need signalling systems

A

Recognise, transfer, amplify signals. Modulate (turn on and off) effector systems. Adapt and respond to changes in the environment

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2
Q

How do we respond specifically to stimuli

A

By selective expression of receptors and molecules involved in signal transduction

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3
Q

What can we not predict

A

Receptor or signalling transduction mechanism from the stimulus

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4
Q

Receptors detect

A

Chemical and physical stimuli

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5
Q

Most receptors are located where?

A

embedded in PM to detect EC signals

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6
Q

Physical interaction of receptor and stimuli provides

A

energy to change the structure of the receptor and so initiate signalling

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7
Q

IC Receptors detect

A

small membrane permeable stimuli e.g. gases and lipids

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8
Q

How many families of receptors in the mammalian genome

A

25

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9
Q

Members of each receptor family share

A

1 or more structurally homologous domains e.g. Ligand BD or signal transducing domains

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10
Q

Ion channels can generate…

A

chemical signals which are changes in the ion composition of cells

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11
Q

Ion channels cause

A

change in potential across the plasma membrane

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12
Q

How many human genes code for membrane channels

A

400

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13
Q

Name the 2 key features of ion channels

A
  1. ion selectivity of pore defined by physical size of filter and amino acids lining the pore
  2. Gating mechanism - voltage or ligand
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14
Q

Evolution of ion channels - 2 examples

A
  1. Duplication of a 2 TMD gave rise to a large family of channels with 2-24 TMD
  2. +ve charges in aa in TM4 gave rise to voltage sensitivity
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15
Q

Ion channel structure

A
  1. subunits come together with a pore in the middle
  2. P loops between 2 TMs creating highly selective filter
  3. on cytoplasmic side, TMs closely packed to form a gate that blocks ion passage
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16
Q

Example of a K ion channel and it’s structure

A 
2 TMD
tetrameric
homomeric
K+ need to dehydrate and pass single file 
Flow is down an electrochemical gradient
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17
Q

Example of a VG ion channel

A

Kv1

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18
Q

Structure of Kv1

A

4 subunits
6TMD
conserved filter and pore region
voltage sensing S4 domain adjacent to pore lining helices of 4 alpha subunits
Inactivation peptide in alpha - swings to block pore if -ve potential
Cytoplasmic beta subunits for extra regulation

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19
Q

What happens to the inactivation peptide of Kv1 when the membrane is depolarised

A

S4 senses this, pulls on S5 + S6 opening the gate

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20
Q

Define ligand gated ion channels

A

Channels gated by an IC generated or EC chemical stimuli

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21
Q

Example of ligand gated ion channel

A

Cyclic nucleotide gated

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22
Q

How many type of cyclic nucleotide gated ion channels

A

2

one by cGMP and one by cAMP

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23
Q

Similarities of cyclic nucleotide gated ion channels to Kv1

A
  1. tetramer
  2. 6TM
  3. S5/6 alpha helical domains
  4. central pore with p loop selectivity filter
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24
Q

Differences of cyclic nucleotide gated ion channels to Kv1

A

Added regulatory domain in the IC N/C terminus
Cyclic nucleotide binding domain IC - C terminus opens pore allowing permeability of Na+/Ca2+
these ions are bigger and so the channel is less selective

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25
Q

How many ligands must bind to cyclic nucleotide gated ion channels to activate them

A

3/4 sites occupies to open channel and cause transformational change and energy to be transduced

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26
Q

What is the conc/response curve of cyclic nucleotide gated ion channels

A

Sharp

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27
Q

Result of calcium binding to cyclic nucleotide gated ion channels

A

bind to N term associated with calmodulin and provides negative feedback

28
Q

What is P2XR gated by and how many bind

A

3 ATP extracellularly

29
Q

Structure of P2XR

A

Trimeric
2 TMD
Homomeric mostly - can be heteromeric

30
Q

What are ionotropic receptors gated by

A

EC ligands

31
Q

Selectivity examples of ionotropic receptors x 3

A
  1. Na+ / K+ selective channels control membrane excitability – depolarize cells
  2. Channels which added permeability to calcium also directly regulate activity of calcium sensitive proteins
  3. Cl- selective channels control membrane excitability – hyperpolarize cells
32
Q

Name of pentameric channels

A

Cys loop

33
Q

Examples of cys-loop channels

A

nAChR
GABAAR
5HT3

34
Q

Location of N/C terminus in Cys loop channels

A

EC, 4TMD

35
Q

Name and examples of tetrameric channels

A

Ionotropic glutamate R i.e. NMDA

36
Q

Location of N/C terminus in tetrameric channels

A

N term EC, C term IC, 3TMD

37
Q

Trimeric channel example

A

P2X e.g. P2XR

38
Q

Glutamate receptor structure

A

Tetrameric
Form as dimers of dimers
Ligand BS in cleft near PM that closes when occupied

39
Q

What happens to glutamate receptor cleft when glutamate binds

A

Cleft closes like a clamshell producing tension on TMD pulling the channel open

40
Q

Glutamate receptors are selective for which ions

A

Na+

K+

41
Q

How were glutamate receptors formed

A

From the fusion of S5-p-S6 and bacterial amino acid binding protein

42
Q

What led to the emergence of different glutamate receptors

A

Multiple genes
Alternate splicing
RNA editing

43
Q

3 Examples of Glutamate receptors

A

NMDA
AMPA
Kainate

44
Q

NMDA is permeable to what

A

Ca2+, Na+

45
Q

Excess stimulation of NMDA leads to what

A

Excitotoxicity

Increasing glutamate, increases Ca2+ –> stroke/neuron death

46
Q

What activates NMDA

A

glycine
glutamate
These need a depolarisation of +30mV to dislodge Mg2= to allow calcium and sodium in

47
Q

Speed of EPSP of NMDA

A

slow

48
Q

Speed of EPSP for AMPA and KAINATE

A

fast

49
Q

Which neurones are AMPA and KAINATE present on

A

AMPA - post synaptic

Kainate - pre and post as inhibit pre synaptic neurons

50
Q

Ampa and kainite allow which ions through the channels

A

Na+, K+ for depolarisation

51
Q

Example of Cys-loop R and its structure/location

A 
nAChR
pentameric 
alpha2, beta, gamma, E
Muscles - has large external N term
IC loop between M3 and M4
TM = M1-M4
52
Q

How many and what does Ach bind to. Result of this

A

2 ACh bind to alpha subunits pocket

causes rotation or twisting motion of M2 subunits opening the pore = permeable to hydrated cations

53
Q

How many subunits in any one ligand-gated ion channel family?

A

Multiple

54
Q

Example of a nAChR and what it is involved in

A

nAChR alpha 4
One of many types in the brain
Involved in nicotine addiction and reward pathways - releases dopamine when nicotine binds

55
Q

How does nAChR of muscle differ to the brain

A

Needs to be near to calcium calcium release machinery

56
Q

Autoimmune loss of nAChR leads to

A

Myasthenia gravis

Epliepsy

57
Q

Mutation leading to epilepsy in nAChR

A

Gain of function increasing excitability –> seizures
In CHRNA4 encoding alpha 4 in brain
= ADNFLE - autosomal dominant nocturnal frontal love epilepsy

58
Q

How many mutations in ion channels found leading to epilepsy

A

9

59
Q

Which receptor regulates LTP required for memory formation

A

Glutamate receptor

60
Q

How do VG and LG ion channels work together

A

LG starts process

VG are the amplification system to generate an AP that spreads and controls contraction or release of NT

61
Q

How do glutamate receptors control memory formation

A
  1. before LTP - probability of vesicle release is low and post synaptic responsiveness is low
  2. With LTP induction, rapid stimulation –> NMDA open –> Ca2+ in –> binds to calmodulin –> stimulates CAM Kinase II –>AMPA phosphorylates
  3. Probability of step 1 is now high
62
Q

Explain contraction of muscles

A

Ap fires, Ca2+ open, Ach vesicles dock, fusion w/membrane, Ach release, activates nAChR, Na+ moves into post synaptic cell, depolarisation

63
Q

Is GABA excitatory or inhibitory

A

Inhibitory NT of vertebrates

64
Q

Two forms of GABA R

A

GABAAR - ionotropic/LG

GABABR - GPCR/metabotropic

65
Q

Pathway of GABA R

A

GABA binds to EC, opens Cl- selective pore, drive rev pot Cl- = -75mV inhibiting firing of new potentials

Cell and molecular extras (16 decks)

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