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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
How many ligands must bind to cyclic nucleotide gated ion channels to activate them
3/4 sites occupies to open channel and cause transformational change and energy to be transduced
26
What is the conc/response curve of cyclic nucleotide gated ion channels
Sharp
27
Result of calcium binding to cyclic nucleotide gated ion channels
bind to N term associated with calmodulin and provides negative feedback
28
What is P2XR gated by and how many bind
3 ATP extracellularly
29
Structure of P2XR
Trimeric 2 TMD Homomeric mostly - can be heteromeric
30
What are ionotropic receptors gated by
EC ligands
31
Selectivity examples of ionotropic receptors x 3
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
Name of pentameric channels
Cys loop
33
Examples of cys-loop channels
nAChR GABAAR 5HT3
34
Location of N/C terminus in Cys loop channels
EC, 4TMD
35
Name and examples of tetrameric channels
Ionotropic glutamate R i.e. NMDA
36
Location of N/C terminus in tetrameric channels
N term EC, C term IC, 3TMD
37
Trimeric channel example
P2X e.g. P2XR
38
Glutamate receptor structure
Tetrameric Form as dimers of dimers Ligand BS in cleft near PM that closes when occupied
39
What happens to glutamate receptor cleft when glutamate binds
Cleft closes like a clamshell producing tension on TMD pulling the channel open
40
Glutamate receptors are selective for which ions
Na+ | K+
41
How were glutamate receptors formed
From the fusion of S5-p-S6 and bacterial amino acid binding protein
42
What led to the emergence of different glutamate receptors
Multiple genes Alternate splicing RNA editing
43
3 Examples of Glutamate receptors
NMDA AMPA Kainate
44
NMDA is permeable to what
Ca2+, Na+
45
Excess stimulation of NMDA leads to what
Excitotoxicity | Increasing glutamate, increases Ca2+ --> stroke/neuron death
46
What activates NMDA
glycine glutamate These need a depolarisation of +30mV to dislodge Mg2= to allow calcium and sodium in
47
Speed of EPSP of NMDA
slow
48
Speed of EPSP for AMPA and KAINATE
fast
49
Which neurones are AMPA and KAINATE present on
AMPA - post synaptic | Kainate - pre and post as inhibit pre synaptic neurons
50
Ampa and kainite allow which ions through the channels
Na+, K+ for depolarisation
51
Example of Cys-loop R and its structure/location
``` nAChR pentameric alpha2, beta, gamma, E Muscles - has large external N term IC loop between M3 and M4 TM = M1-M4 ```
52
How many and what does Ach bind to. Result of this
2 ACh bind to alpha subunits pocket | causes rotation or twisting motion of M2 subunits opening the pore = permeable to hydrated cations
53
How many subunits in any one ligand-gated ion channel family?
Multiple
54
Example of a nAChR and what it is involved in
nAChR alpha 4 One of many types in the brain Involved in nicotine addiction and reward pathways - releases dopamine when nicotine binds
55
How does nAChR of muscle differ to the brain
Needs to be near to calcium calcium release machinery
56
Autoimmune loss of nAChR leads to
Myasthenia gravis | Epliepsy
57
Mutation leading to epilepsy in nAChR
Gain of function increasing excitability --> seizures In CHRNA4 encoding alpha 4 in brain = ADNFLE - autosomal dominant nocturnal frontal love epilepsy
58
How many mutations in ion channels found leading to epilepsy
9
59
Which receptor regulates LTP required for memory formation
Glutamate receptor
60
How do VG and LG ion channels work together
LG starts process | VG are the amplification system to generate an AP that spreads and controls contraction or release of NT
61
How do glutamate receptors control memory formation
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
Explain contraction of muscles
Ap fires, Ca2+ open, Ach vesicles dock, fusion w/membrane, Ach release, activates nAChR, Na+ moves into post synaptic cell, depolarisation
63
Is GABA excitatory or inhibitory
Inhibitory NT of vertebrates
64
Two forms of GABA R
GABAAR - ionotropic/LG | GABABR - GPCR/metabotropic
65
Pathway of GABA R
GABA binds to EC, opens Cl- selective pore, drive rev pot Cl- = -75mV inhibiting firing of new potentials

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