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LIFE > Part II: Receptors, Ion Channels and Signalling > Flashcards

Part II: Receptors, Ion Channels and Signalling Flashcards

1
Q

What are GPCR involved in

A

Senses, autonomic function

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2
Q

GPCR structure

A

Single polypeptide in an anticlockwise bundle, 7 (α-helices) transmembrane spanning domains, extracellular N terminus, intracellular C terminus and 3 extra (ECL) and intracellular loops (ICL)

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3
Q

Another name for GPCR

A

7 transmembrane domain receptors

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4
Q

5 families of GPCR and info abt them

A

1) Family A “Rhodopsin” = most common. 2) Family B “Secretin”: Some peptide hormones. 3) Family C “Glutamate”: Glutamate + GABA neurotrans in brain. Calcium + some taste receptors. 4) “Frizzled”: Receptors in development, bitter taste receptors. 5) “Adhesion”: Cell-cell adhesion and motility

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5
Q

How does the rhodopsin (A) family bind ligands

A

Mostly small molecs: Binding site within transmembrane domain bundle. Medium sized ligand sites involve bundle and receptor ECL domains + N terminus. Largest = N-terminus built to generate a binding site

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6
Q

How does Glutamate (C) family bind to ligands

A

To small molecules but have a large N terminus called Venus Fly Trap (VFT) domain. It closes around the ligand to activate the recptor.

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7
Q

Types of bonds on binding site

A

Ionic: +ve charge NH3+ with COO- amino acid, Hydrogen bonds, Hydrophobic bonds with benzene rings

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8
Q

What is receptor mutagenesis

A

Change amino acid you think is important on binding site by genetic engineering. Eg change OH group to CH3. Then run competition binding study to find if it made a difference.

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9
Q

How can GPCR structures be seen/visualised

A

X ray crystallography

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10
Q

What is an allosteric modulator

A

Binds to a separate site from agonist orthosteric site. Changes nature of response to orthosteric agonist. Can alter orthosteric ligands affinity (ability to bind) / acitvate receptor/both

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11
Q

What are positive/negative allosteric modulators

A

Positive: enhances agonist effect. Negative: inhibits agonist effect

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12
Q

What is co-operativity for allosteric modulators

A

Orthosteric + allosteric ligands influence each other. Positive coop for PAMs (ennhances agonist effect) + negative for NAMs

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13
Q

How can an allosteric modulator prevent the dissociation of agonist

A

Bind above binding bocket so its locked in. Enhances the affinity

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14
Q

Benefits of allosteric modulation

A

Increased selectivity: Agonist needs to be present otherwise no effect. Allosteric sites may be unique to receptor subtype. Controlled response: Max effect is limited. Reduces risk of receptor over stimulation

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15
Q

Conformational change of GPCR during activation of drug+receptor

A

Extracellular domain with drug moves inward. Intracellular moves away from each other allowing effectors such as G proteins to be recruited

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16
Q

What are heterotrimeric G proteins

A

GPCRs activate them. G proteins made of 3 subunits where at least 1 is different from the other 2

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17
Q

What are the G protein subunits

A

Gα: Binds guanine nucleotides (GDP/GTP). Gβ + Gγ: Always form a dimer (Gβγ)

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18
Q

Where are Gα and Gβγ located

A

On intracellular side of plasma membrane (using lipid anchors)

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19
Q

What is the G protein cycle

A

1) When GPCR inactive, Gα binds GTP and forms a heterotrimeric complex with Gβγ. 2) Activated GPCR catalyses exchange of GDP for GTP on Gα by conformational change. 3) Gα-GTP & Gβγ separate from each other. 4) Gα-GTP & Gβγ activate effector proteins along membrane. 5) GTPase activity of Gα converts bount GTP back to GDP. 5) Gα-GDP reassociates with Gβγ.

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20
Q

3 main Gα classes

A

Gsα: stimulates adenylyl cyclase whcih increases cyclic AMP. Giα: inhibits adenylyl cylcase - decreases cyclic AMP eg smooth muscle contaction, inhibits transmitter release. Gqα: stimulates phospholipase C - enhanced transmitter release, increases intracellular Ca2+, smooth muscle contraction

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21
Q

ATP -> cAMP -> response -> break down cycle

A

ATP + adenylyl cyclase enzyme -> cAMP. Protein kinase A (PK A) forms an inactive tetramer of 2 regulatory + 2 catalytic subunits. cAMP binds to regulatory -> dissociates tetramer, releases active catalytic subunits. PK A phosphorylates target protein -> response. cAMP broken down by phosphodiesterase -> AMP -> ATP

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22
Q

cAMP pathway in Gs coupled receptors

A

Gsα-GTP releases from acitvated receptor. Activates adenylyl cyclase which generates cAMP from ATP. cAMP binds to regulatory subunits on Portein kinase A which releases activates catalytic. They phosphorylate target proteins

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23
Q

cAMP pathway in Gi coupled receptors

A

ATP is stopped from converting to cAMP bc adenylyl cyclase is inhibited

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24
Q

Calcium pathway by Gq couple receptors

A

Gqα-GTP activates phospholipase C (PL C) enzyme. This hydrolyses plasma membrane lipid (PIP2). This releases 2 intracellular messengers: IP3 = diffusable out into cytoplasm & DAG = fatty acid tails kept in membrane. IP3 releases Ca2+ from intracellular stores in endoplasmic reticulum into cytoplasm. DAG activates protein kinase C (PK C) which goes to own target for phosphorylation.

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25
Desensitisation/tolerance of receptors definition
Sustained or repeated agonist exposure often leads to reduced responses (all types of receptor)
26
Difference between desensitisation and tolerance
Tolerance is over a longer time-scale: days/weeks not s/mins
27
Mechanism of β-arrestin / desensitisation of GPCRs
1. Uncoupling from G protein: GPCR phosphorylated by GPK kinase attached to βγ. β-arrestin binds to phosphorylated receptors - same place to block G protein. 2. Removal of receptor from cell surface. β-arrestin targets GPCRs for endocytosis (brings them into cell). 3. Internalised receptors degraded by lysosomes (downregulation - long term decrease in receptors) or recycled by dephosphorylation. Alterations in synthesis of new receptor proteins
28
What is downregulation
G prot coupled internalised receptors are degraded by lysosomes - decreases receptor number
29
What is endocytosis
When cell forms a vacuole (pore) to take in matter into cell
30
2 ways ions can pass the lipid bilayer
Transporters (conformational change to take them through it) or channel protein (pore formed - can passively diffuse or is regulated w gating)
31
How is active transport done through lipid bilayer
Using transporters
32
How are active transporters and ion channels complementary
Transporters create the conc gradient that drive ions through open ion channels thus generating electrical signals
33
2 type of membrane channels
Gap junctions & ion channels
34
Difference between cytosol and cytoplasm
Cytoplasm contains cytosol, organelles etc except the nucleus. Cytosol is the liquid component of cytoplasm with no organelles.
35
What are gap junctions
Cell-cell comunnications, large and permissive pores. They connect cytoplasms of 2 cells
36
What are ion channels/what they do
Connect the cytosol to extracellular space, narrow + highly selective pores, mainly inorganic ion passage. Not coupled to energy source
37
Are ion channels/transporters quicker
Ion channels - about 10^5 times quicker
38
What are active vs passive ion channels
Active: Gates can open or close. Passive: (leakage) always open, ions pass through contiuously
39
Ion channel components
1. Transmembrane pore: Selectrivity for charge and size of ion 2. Sensor switch for gating: Membrane potential sensor (voltage-gated ion chan) or neutrotransmitter binding site (ligand-gated ion chans) 3. Regulation mechanisms: In built inactivation switches (open/closed/inactive). Modulation (G proteins, 2nd messengers, protein kinases that can change function of channels. Localisation (where it is)
40
2 ways membrane potential arises
Active electrogenic pumping and passive ion diffusion. Intracellular space negative relative to outside
41
What is passive ion diffusion
Largest contribution to electrical potential across membrane. K+ tends to leave due to conc gradient
42
What is electrogenic ion pumping
Involves Na+, K+, ATPase. Actively pumps 3 Na+ out against electrochemical gradient and 2 K+ in
43
Structure of K+ ion channel
2 sets of Outer helix connected to pore helix connected to inner helix. Betw pore and inner helix there is a selectivity loop with C=O. In between sets there is a vestibule with a pore on either side where ions travel through. It has a selectivity filter where C=O are on the other side.
44
Explain permeability for K+ but not Na+ in ion channel
Ions dehydrated in selectivity filter. Dehydration energy balanced by interaction of ions with carbonyl oxygens. Na+ is too small to interact with all oxygens so only enters at greater energetic expense.
45
3 (4) types of ion channel gating
Voltage-gated, ligand-gated (extra/intracellular ligand), mechanically gated
46
Voltage gated ion channels structure
4 subunits in a circle of 5 transmembrane domains + P loop + S6 transmembrane domain. S1 starts intracell with NH3+ and inactivating particle. P loop lines pore and provide selectivity filter. S6 ends with COO- (C terminal domain) intracellular. S4 contains positively charged amino acids.
47
How does voltage gated ions go from resting to active
When membrane is depolarised and more positive intracellular, S4 (positively charged) repells -> conformational change -> opens pore. +ve ions can go through into selectivity filter
48
How does voltage gated ion channel become inactivated
Inactivating particle blocks channel + passage of ions
49
How is info transmitted along axon
Axon has myelin sheets (make schwann cell). Gap between cells is node of Ravier. Apot signal jumps between the nodes. After ligand gates are activated, get inactivated and signal can't go backwards. Propagation of AP must go forwards where resting gates are present.
50
What is the name if a drug blocks channels by active and inactivated channels
Use dependent
51
2 main types of Ca2+ ion channels
L-type: cardiac, smooth muscle. N-type: Neurons
52
How does K+ channels cause hyperpolarisation + depolarisation
Efflux (flowing out) = hyperpol where intracellular is more negative. Channel block results in depolarisation = closer to 0
53
AP repolarisation with K+ gated channels
Na+ chans open, Na+ enters. AP increases. Na+ close. K+ opens, K+ leaves cell. AP decreases. Overshoots but eventually evens out to resting potential
54
Structure of resting chemical synapse
Nerve terminal of presynaptic cell constains synaptic vesicles (pockets) containing neurotransm. In between presyn and postsynaptic target cell is synaptic cleft. Then transmitter-gated ion chans are on the postsyn cell
55
3 types of ligand gates
NT receptor, Ca2+-activated K+ channel, cyclic nucelotide gated channel
56
What is a metabotropic receptor
It requires eg G proteins and second messengers to indirectly modulate ionic activity in neurons
57
Why do some transmitters activate both GPCRs and ion channels
Ion channels are much faster eg for synaptic transmission
58
Structure of ligand gated ion channels
4 transmem domains connected to extracellular N terminal and C terminal. Between N and 1st transmem is binding site. 2nd transmem forms the pore lining. 5 of these subunits together make whole receptor. Differerent types of subunits make slighlty different channels.
59
Difference between AMPA and NMDA as glutamate receptor channels
AMPA activated by glutamate and is highly permeable to Na+ so Na+ enters cell. NMDA activated by glutamate and glycine as coactivator/cofactor. Permeanle to Na+ AND Ca2+. Depolarisation (+ve in, -ve out) needed for activity because Mg acts as blocker. Ca2+ can act as a second messenger
60
What does it mean if a channels is permeable to an ion
It lets it through in the selectivity filter
61
What is Long-term potentiation (LTP)
Synaptic plasticity formed after repeated activation. SIngle AP cause greater enhanced response in postsynaptic cells
62
AMPA-NMDA working together which causes long-term potentiation
AMPA lets Na+ in -> depolarisation. Causes Mg2+ block in NMDA to be removed. Allowes Ca2+ to enter cell -> 2nd messenger cascades -> drives insertion of more AMPA receps on plasma membrane = increases cells sensitivity to glutamate
63
What is excitotoxicity
Pathological process in which neurons are damaged by overactivation of excitatory ligand gated ion channels
64
What are excitatory receptors
Let +ve charged ions into postsynaptic cell -> depolarisation that excited the neuron
65
What does an inhibitory lig gated ion channel do, eg GABA
Permeable to Cl- -> hyperpolarisation
66
What can high [Ca2+] cause
Precipitation of phosphates, aggregation of proteins and nucleic acids, disruption of lipid membranes
67
Explain origin of Ca2+ as an intracellular signal
Low [Ca2+] in ocean in beginning meant low cytosolic levels. Then Ca2+ from Earths crust and decreased akalinisation of oceans -> increase of Ca2+ in oceans. Evolution of Ca2+ homeostatic system -> transmembrane Ca2+ gradient -> Ca2+ signalling -> Ca2+ permeable channels
68
69
Ca2+ On-mechanisms
Voltage & ligand gated ion channels, g-prot coupled receps that activate ion channels, IP-3 receptors in the ER (endoplasmic reticulum), ryanodine receptors in the ER
70
Ca2+ Off-mechanisms
Ca2+ pumps on cell membrane (w ATP), mitochondrial Ca2+ importers, ER (endoplasmic reticulum) Ca2+ pump (w ATP), Na+/Ca2+ exchanger, Ca2+ binding molecule as buffer
71
What happens with ryanodine receptors in the endoplasmic reticulum
Ca2+ enter cytoplasm which binds to ryanodine receptors to release more Ca2+ from endoplasmic reticulum into cytoplasm
72
5 interactions of Ca2+
cyclic AMP, activate NO synthesis, PI3 kinase, feedback interactions = Ca2+ modulates its own activity, mitogen-activated protein kinase
73
What are Ca2+ microdomains
Sites in a cell's cytoplasm with a localised high calcium ion concentration. They are found immediately around the intracellular opening of calcium channels
74
4 main things about catalytic receptors
Closely linked to enzyme activity, dimerisation of receptor, most messengers = peptides or proteins, long-term processes like growth + gene expression
75
Main classes of catalytic receptord
Guanylyl cyclase receps, receptor Tyrosine kinases
76
2 classes of GC receptors
Membrane bound and cytoplasmic
77
3 types of membrane bound GC receptors
GC-A, GC-B, GC-C.
78
3 types of peptides that GC receps respond to and ifthey are GC-A or GC-C
Atrial natriuretic peptide (ANP) (GC-A), Brain natriuretic peptide (BNP) (GC-A) and Uroguanylin (GC-C)
79
Purpose of Atrial natriuretic peptide (ANP) + how it works
Released from distended (swollen bc too much blood in heart) atria as a hormone -> Renal (kidney) and vascular GC-A receps -> Excretion of fluit + salt to lower blood volume in heart -> vasodilation
80
Use of Brain natriuretic peptide (BNP)
Neuromodulator
81
Use of uroguanylin
Intestinal epithelial secretion. GC-C receps also activated by bacterial enterotoxins (diarrhoea)
82
What is an enterotoxin
A substance that is harmful to your digestive system. It is produced by certain bacteria.
83
Info about cGMP + comparison to cAMP
Activates Protein Kinase G (PKG) as opposed to PKA. Degraded by phosphodiesterase (PDE5) - same for cAMP. Often have smilar effects when concs are elevated
84
Effect of cGMP in membrane bound GC receps
Protein kinase G activated -> vasorelaxation + dilation of vascular smooth muscle. AND Fluid and sodium secretion by kidney epithelial cells. Reduces blood volume
85
What are gasotransmitters
Gases used as messenger + signalling molecules
86
How does NO promote vasorelaxation
Synthesised + released by vascular endothelium cells. Diffuses into vascular smooth muscle cells
87
3 uses of NO
neuromodulator, immune system regulation, blood vessel tone
88
How NO is synthesised in endothelium (in vessel)
Activation of Gq-coupled GPCR -> elevates [Ca2+] -> NO synthase enzyme activated -> release of NO from L-arginine being converted to something else
89
What happens with No in vascular smooth muscle cells
NO stimulates cytoplasmic "soluble" guanylyl cyclase -> elevade intracellular [cGMP] -> activate protein kinase G -> smooth muscle relaxation. PDE5 isoform breaks down cGMP
90
Another way to describe receptor tyrosine kinases + examples of what it controls
Growth factor receptors. Cell survival, proliferation (growth of cells) differentiation, metabollism - long term
91
Explain activation of receptor tyrosine kinsases (EGFR)
Epidermal Growth factor (EGF) binds. Receptor dimerises. Tyrosine kinase (an enzyme) of one receptor phosphorylates its partner + vice versa (autophosphorylation). Signalling proteins recruited containing SH2 domain - recognises phospho-Tyr and surrounding amino acids in receptor (specificity)
92
What are EGF, NGF, BDGF, VEGF in receptor tyrosine kinsases.
Epidermal growth factor, nerve, brain derived GF, vascular endothelial GF
93
What gives RTK specificity
The SH2 domains that recognises the amino acid sequences - recruits different signalling proteins w different combination of SH2 domains
94
Difference between phospholipase Cɣ and C
Cɣ is an RTK specific form containing SH2 to bind to receptor. Then both same: metabolises PIP2 - releases PK C + IP3 = intracellular messenger to release Ca2+ from intracell stores. PK C phosphorylates target proteins
95
2 types of SH2 proteins + example
1. Ones that have their own enzyme activity - directly produces signals in cells. Eg phospholipase Cɣ 2. Adaptor proteins that link RTK with signalling proteins. Eg MAP kinase
96
What does MAP kinase stand for + its use
Mitogen (substance that induces mitosis) Activated Protein kinase. Gene expression, nuclear transcription factors, cell survival, activity of cytoplasmic proteins
97
MAP kinase pathway
Grb2 with HS2 domain interacts with autophosp receptors. Brings SOS. SOS is GNEF for Ras. Exchnages Ras GDP to Ras GTP. Ras GTP binds to Raf to activate it. Raf phosphorylates and activates MEK --> same to MAP kinase -> same to Transcription factors (gene expression) + Cytosolic proteins (protein translation)
98
On and off switch for Ras GTP
On: Guanine Nucleotide exchange factors (GNEFs) that accelerates Ras GTP binding to Raf. Off: GTPase activating proteins (GAPs) - turns it to Ras GDP
99
What is Ras and how is it used in MAP kinase pathway
Membrane-bound monomeric G protein. Ras-GTP (guanisin tri phosphate) = active, Ras GDP=inactive
100
How can PK C affect MAP kinase pathway
Can phosphorylate Raf to enhance activity
101
Difficult to produce synthetic drugs at RTKs
Need large binding sites, difficult to replicate w small molecules. TK catalytic domain ATP binding sites are similar - harder to obtain selective molecules
102
Antibody structure
Fab: Antigen binding fragment domain. On top of Y. Variable region, binds to antigen (recognition). Has hypervariable regions on top - binding surface and vary due to complex gene organisation (bivalent aka one on each strand). Fc: Constant fragm domain. directs immune cells to target (binds to effector cells)
103
Advantages of igG receptord
For receps with large binding sites, higher affinity + selectivity betw closely related receptors (eg tyrosine kinase), diff mechanisms of action
104
What does inhibiting VEGF receptor activation cause
Inhibit tumor angiogenesis = formation of new blood vessels
105
What is proliferation
rapid reproduction of a cell, part, or organism (often tumours)
106
How did imatinib help chronic myeloid leukaemia (CML)
First anti cancer TyrK inhibitor. Chromosomal translocation (9 & 22) -> produced Philadelphia chromosome when BCR + ABL genes put together - overexpressed ABL (kinase protein) -> tumour. Imatinib is selective Abl tyrosine kinase inhibitor.
107
What does vemurafenib do
Small molec inhibitor of B-Raf V600E (mutated amino acid). B-Raf V600E leads to activation of Ras-MAPK pathway + proliferation so vemurafenib binds selectively to mutated form.
108
Another description for nuclear receptors
Receptors that are ligand regulated transcriptions factors
109
How do nuclear receptors work
Receptors in cytoplasm. Lipphilic ligands eg steroid hormones pass through membrane and bind. Translocation of proteins to nucleus and bind DNA as dimers -> promotes transcription of specific target genes -> mRNA -> protein synthesis
110
What is structure of oestrogen receptor
single polypeptide w 3 domains. N--AF1--Zinc finger--AF2. AF="activation fucntion". Zinc finger = DNA binding domain - recognises specific nucleotide sequence. AF2 forms ligand binding site
111
Structure of DNA + oestrogen receps (ER) for transcription
2 estrogen dimers bind to promotor sequence = palindromic so same sequence on both strands but from either direction. Then comes RNA polymerase: ER regulates binding of RNA polymerase to TATA box = (initiation for transcription).
112
What type of proteins can oestrogen recruit for transcription
Co-activator/co-inhibitor proteins
113
What are SERMs
Selective estrogen receptor modulators (SERMs) are a type of hormonal therapy medicine used to treat estrogen receptor-positive breast cancer
114
How does tamoxifen act in the body
ER antagonist in breast tissue - inhibits proliferation. ER agonist in bone tissue (recruits co-activator proteins) - helps prevent bone loss
115

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