Cell Signalling Flashcards
(124 cards)
1
Q
What are inotropic receptors
A
Receptor which binds to an agonist which is an ion channel
2
Q
What is a metabotropic receptor
A
A receptor that binds a ligand which triggers a cascade of reactions
3
Q
What are the forces that effect the opening of an ion channel
A
Chemical gradient and electrical gradient
4
Q
What is the reverse potential
A
The point at which the forces are equal = no movement of ions
5
Q
What is the resting membrane potential
A
The average of resting potentials of the open ion channels
6
Q
Which receptors are non specific cation channels
A
Glutamate and Ach receptors
7
Q
What are non specific cation channels
A
Not specific to ions and have a reversal potential close to 0
8
Q
Where are Ach receptors found
A
NMJ in muscle cells
Between pre and post synaptic cells in the ANS
9
Q
What ions are Ach receptors permeable to
A
Na+, K+, Ca2+
10
Q
What part of the Ach receptor allows it to bind to Ach
A
Alpha subunit - each Ach molecule can bind 2 receptors
11
Q
Name an Ach antagonist and how it works
A
Alpha-bungarotoxin
Blocks the ability of the nerve to control the muscles
Causes paralysis
12
Q
What receptors have a pentameric structure
A
GABA glycine and nicotinic Ach receptors
13
Q
What is the importance of the amino acids that line the pore of the receptors
A
They dictate if they let through anions or cations
14
Q
What is the importance of the lock an key mechanism on receptors
A
Affect wha can bind/modulate the activity of the receptors
15
Q
Why are GABA and glycine receptors inhibitory
A
Ecl is close to Em and below the action potential threshold -> prevents action potentials from happening
16
Q
Why is subunit composition important
A
Subtle variations can affect the receptor properties e.g sensitivity to ligands
17
Q
What do GABA-R subunit composition dictate
A
Receptor properties, dynamic variations and cell surface distribution
18
Q
How does the location of the delta subunit in GABA-R relate to its functions
A
Placed outside of the cell and doesn’t contact much GABA
Monitors the ambient level and persistently open if GABA present
19
Q
How does the location of the beta subunit in GABA-R relate to its functions
A
At the synapse and come in contact w lots of GABA
Open at precise moments and quickly close
20
Q
Describe purinergic receptors
A
Excitatory receptors w ATP as their ligand
Permeable to cations
Expressed in the brain
21
Q
What is glutamate
A
A principal excitatory neurotransmitter in vertebrate nervous systems
22
Q
Describe ionotropic glutamate receptors
A
The ion channel is the receptor
Lined w negatively charged amino acid subunits
Allows cation to pass through to generate an excitatory subunit
23
Q
What are the 3 main classes of glutathione receptors that are defined by man made agonists
A
AMPA, NMDA, kainate receptors
24
Q
Which agonists activate all 3 classes of glutamate receptors
A
Glutamate and kainate
25
Where are AMPARs and NMDARs usually co-localised
At synapses where they mediate fast chemical synaptic transmission
26
Why are AMPARs and NMDARs needed at the presynaptic terminal
To act as auto receptors -> glutamate binds on the presynaptic site
27
Describe the structure of iGluRs
Have 4 subunits and 3 transmembrane domains (TM1, TM3, TM4) with a re-entrant loop (TM2)
28
What is the importance of the extracellular domain in iGluRs
Create the glutamate binding site
29
What is the importance of the transmembrane loops in iGluRs
Create the shape of the pore
Important for various intracellular processes
30
Where does glutamate bind on iGluRs
Between the S and S2 extracellular domains
Each subunit can bind 1 molecule
31
What subunits make up AMPARs
GluA1 - GluA4
Variants of the same protein that bind together to form the receptor
32
What mutations can the AMPARs subunits undergo
Alternative splicing and RNA editing
33
What channels can the AMPARs form
Homomeric; 1 type of subunit
Heteromeric; mix of subunits
34
Why is the GluA2 subunit important in AMPARs
It determines the current/voltage curve
Dictates the reversal potential and affects Ca2+ permeability
35
What are the AMPARs splice variants
2 exon; flip and flop which can affect receptor kinetics
36
What determines the rate of AMPARs desensitisation to glutamate
The subunit composition and flip/flop variant
37
Which subunit is affected by flip and how
The GluA4 subunit
Flip variant lengthens time the receptor is open
38
Describe how the AMPAR becomes desensitised to glutamate
When glutamate is maintained at receptor it doesn’t maintain current
The ion channel close even though glutamate is bound
39
Which subunits of AMPAR are permeable to Ca2+
GluA1 and GluA3
40
Why are many AMPARs impermeable to Ca2+
They contain a GluA2 channel
41
How can GluA2s permeability to Ca2+ be altered
Glutamine at the pore is flipped to arginine
42
What dictates the functionality of NMDARs
Mg2+
Drawn in by the negative field which depolarises cell
Negative field now has less influence so Mg2+ forced out
Leaves the pore open
43
Compare the I vs V relationship for AMPARs and NMDARs
AMPAR; linear relationship
NMDAR; non linear relationship
44
How is the NMDAR conditional
Requires the presence of glutamate and for the cell to depolarise
45
What is the purpose of phosphoinositide signalling
To keep [cystolic Ca2+] low to prevent Ca2+ and excess phosphates bonding to form a precipitate
46
How does the Ca-ATPase pump work
Pumps Ca2+ out of the cell using energy from ATP -> ADP hydrolysis against Ca2+ conc gradient
47
What is the Ca-ATPase in the plasma membrane called
PMCA
48
What is the Ca-ATPase in the ER called
SERCA
49
What does the SERCA pump do
Pump Ca2+ from the cytosol into the ER or the SR in a muscle cell
50
How does the Na/Ca exchanger work
Removes Ca2+ from the cell by exchanging them for Na+
Uses inward Na+ gradient generated by Na/K pump
51
Why is the mitochondria important in maintaining a low cystolic Ca2+ conc
Take up Ca2+ when the SERCA and PMCA become saturated
52
Describe the function of calmodulin
Sensor protein which undergoes conformational change when bound to Ca2+
Trigger downstream physiological responses
53
What is the function of buffer proteins
Bind to Ca2+ and act as aa sponge to bring down cytosolic [Ca2+]
54
Why does the cell need a range of mechanisms to bring down cystolic [Ca2+]
So the cells can remove the ions over a wide range of [Ca2+]
55
Where are IP3Rs and RyRs located
On the membrane of ER/SR
56
What is the secondary messenger for IP3Rs
IP3 and Ca2+
57
What is the secondary messenger for RyRs
Ca2+
58
What are the 3 types of Ca2+ signals
Elementary events
Global Ca2+ wave intracellular
Global wave Ca2+ intercellular
59
Describe an elementary Ca2+ event
Very small and doesn’t take up the entire cell
Ca2+ rise is highly located in the cell
60
Describe a global Ca2+ wave intracellular
Ca2+ waves happens in part of the cell and makes it way a cross the whole cell
61
Describe a global Ca2+ wave intercellular
The Ca2+ wave doesn’t stop at the boundary of the cell it propagates across the mono layer of cells
62
Describe how a signal binding to a GCPR causes Ca2+ release from the ER/SR
Signal binds GCPR -> activates phospholipase C-beta
Clips PIP2 molecule -> DAG and IP3
IP3 released into cytosol and diffuses to IP3R on ER/SR
Opens channel to release Ca2+ from ER/SR
63
What happens to DAG when it’s produced from PIP2
Stuck in the plasma membrane and tries to find PKC its target protein
64
Why does DAG remain in the plasma membrane
Due to its hydrophobic fatty acid chains
65
How does a Ca2+ signal present itself
Series of spikes that will persist as long as a the hormone is present
66
What effect will doubling the [hormone] on the Ca2+ spikes
Amplitude remains constant
Frequency will increase
67
Describe CICR
Ca2+ released from the ER stimulates further Ca2+ release from neighbouring IP3Rs
Feeds forward to release more Ca2+
68
What are the 2 components to a Ca2+ signal
Temporal (spike) and spatial (wave)
69
Describe how a Ca2+ spike and wave are linked
When spike begins = initiation of Ca2+ propagation
Midway through spike = mid propagation halfway through the cell
Peak = whole cell is full of Ca2+
70
What buffers/prevents the diffusion of Ca2+ through the cell
Buffered by binding to buffer proteins = no wave/spike
71
What needs to happen to generate a Ca2+ wave/spike
CICR needs to overcome the buffer proteins momentarily to generate wave/spikes
72
What needs to take place for the falling phase of the Ca2+ spike
IP3Rs stop releasing Ca2+ to allow the off mechanisms to remove Ca2+
73
What happens in between Ca2+ spikes
Cell at rest and off mechanisms relax which allow the cell to produce another Ca2+ spike
74
What is the suggested stimulus for RyRs
CADPR
75
Why is IP3 required for CICR to be triggered
To sensitise the receptor and Ca2+ for CICR
76
How does RyRs differ from IP3Rs
RyRs don’t need cADPR to sensitise the receptor in order to behave as a CICR channel
IP3Rs need IP3 to be able to behave as a CICR channel
77
Why do RyRs and IP3Rs require ATP
As aa safety mechanism
78
How does ATP work as aa safety mechanism for RyRs and IP3Rs
If cell has plenty energy then there will be ATP present
If low ATP - site wont be occupied on receptor so no movement of Ca2+
= no Ca2+ signalling
79
What is a Ca2+ puff
When Ca2+ is released from a cluster of 10 IP3Rs
80
What is a Ca2+ spark
When Ca2+ is released from a cluster of 10 RyRs
81
What is an abortive Ca2+ wave
When the wave is borderline before intermediate/high level of hormones
Wave only propagates across part of the cell not the full wave
82
How are puffs and sparks forerunners for a Ca2+
Sensitise the IP3R so that if the hormone stimulus increases, the channels can produce a CICR
83
What is a Ca2+ blip
A fundamental event released as a result from only 1 IP3R
84
What is a quark
A fundamental event released as a result from only 1 RyR
85
How can a Ca2+ dependent response be triggered i.e wave not necessary
Ca2+ spark in muscle -> Sr releases Ca2+ near membrane
Spark close to the Ca2+ activated K+ channel
Activates the channel = cell hyperpolarisation = muscle relaxation
86
How does a global Ca2+ effect differ to aa spark in muscle cells
Global = contraction
Spark = relaxation
87
How can a Ca2+ wave propagate though cells
IP3 and Ca2+ are needed to diffuse through gap junctions
88
How do the cilia of different cells coordinate a response
Through Ca2+ intracellular wave events
89
Describe a cell specific calcium signalsome
Defines the precise isoforms of each component that is any given cell
90
What are the 2 types of remodelling signalsomes undergo
Phenotype and genotypes remodelling
91
What is phenotypic remodelling of a signalsome
when the component become phosphorylated which can change its activity
92
What is genotypic remodelling of a signalsome
Somatic mutations in single cells alter activity of a component and are passes on from one generation to the next via germline mutations
93
Describe how phenotypic remodelling allows the heart to have stronger/larger contractions
CAMP dependent reversible phosphorylation of key Ca2+ signalling components
= enables more Ca2+ to enter the cell and more pumped out to generate larger Ca2+ signals
94
What drives liver regeneration
Down regulation of key Ca2+ signalling components
95
How does Alzheimer’s disease affect memory
Extracellular plaque deposits of beta amyloid peptide which aggravates outside of nervous cells to disrupt synaptic transmission
96
How does APP and beta amyloid affect the cytosolic Ca2+ levels
Up regulation of Ca2+ signalling
Beta amyloid oligomers increase Ca2+ entry via the NMDAR
APP increase Ca2+ release from stores
97
What happens to APP once it has been metabolised
Makes its way to the nucleus to act as a TF and increase the txn of RyRs and decrease txn of calbindin
98
How does APP result in amyloid dependent Ca2+ signalling
Increase Ca2+ leak through RyR into cytosol
Decrease in Ca2+ buffering
= [Ca2+] in nervous cells
99
How are memories formed
Triggered by a strong Ca2+ signal through NMDAR through the LTP
Initially enter temporary memory store but are consolidated into the permanent memory store at night
100
How does Ca2+ erase the temporary memory store
Broader raise of Ca2+ but at a lower signal triggers LTD
Erases temporal memory store so it is ready to receive new temporary memories
101
How does Alzheimer’s affect memory
Increased level of resting Ca2+ so there is still LTP during the day but there is persistent activation of LTD
= erasing of temporary memory store before it can be consolidated to permanent store
102
How can vitamin D potentially reverse Ca2+ dependent neuro-degeneration
Increases the expression of plasma membrane ATPase and Na/Ca+ exchanger
Increases [calbindin]
= decrease in resting cytosolic [Ca2+]
103
How does positive feedback make it hard to perceive the primary cause of Alzheimer’s
Amyloid stimulates an increase in Ca2+ which can stimulate APP which also increases Ca2+
104
What is Brody myopathy
Skeletal muscle genetic disorder characterised by stiffness and cramp
105
What causes Brody myopathy
Mutation in SERCA1pump therefore can’t pump out all the Ca2 back into SR
Impedes relaxation
106
What are the 2 types of adenylyl cyclase
Plasma membrane form
Soluble form
107
How is the membrane bound from of adenylyl cyclase activated
By the alpha s subunit on GPCR which causes a conformational change
Allows the catalytic subunits to come together
108
What is the reaction to form cAMP
ATP -> cAMP and pyrophosphate via adenylyl cyclase
109
How can forskolin activate all isoforms
Bypasses receptor - GCPR complex and binds directly to adenylyl cyclase
110
What is the role of PDEs
To breakdown cAMP and some can breakdown cGMP
111
Why are PDEs important
Can affect the duration of cAMP rise and how the cAMP level can rise
Alerts the spatial localisation of the cAMP signal
112
What are the 3 off mechanisms for cAMP signalling
PDEs
Inhibit cAMP production
CAMP removal
113
How can cAMP production be inhibited
Some GCPR agonist activate the Gai to reduce AC activity by binding to AC
114
How can cAMP be removed from the cell
MRP transporters that pump cAMP out of the cell
115
What affect does cAMP removal have on the signal
Affects the duration and amplitude of signal
Can impact on spatial aspects
116
What suggests that cAMP signalling is compartmentalised to micro domains and are agonist specific
Different agonists increase cAMP levels but produce different response in same cell
Some agonists produce cAMP dependent responses but do not change global cAMP levels
117
How can cAMP signalling be compartmentalised
AKAPs bind to PKA and have a target domain which allows them to be brung closer to their substrates
Help assemble signalsomes
118
What are the 2 forms of PKA
Type 1 and type 2
119
Describe type 1 PKA
Inactive PKAA binds to cAMP binding domains which releases the catalytic domain to phosphorylate other molecules
120
Describe type 2 PKA
Bind to AKAPS via docking domain but catalytic domain isn’t released
AKAPS bring PKA closer to the substrate
121
Where are beta adrenergic receptors located in a muscle cell and why
Localised near the T tubule where all the excitatory contraction machinery is located
122
Why do prostanoid receptors excitation not lead to a contraction
Localised in different regions and phosphorylate metabolism enzymes not contraction machinery
123
What leads to PKA dependent phosphorylation of key Ca2+ components in a muscle cell
Beta adrenergic stimulation -> increased elevations in cAMP
124
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