Receptors and enzymes, transporters and ion channels Flashcards
(194 cards)
1
Q
how many main types of receptors are there?
A
4
2
Q
where are receptors found and what is the exception to this?
A
in the cell membrane
except nuclear receptors
3
Q
4 main types of receptors
A
ligand-gated ion channels
GPCRs
enzyme/kinase linked receptors
nuclear receptors
4
Q
most common type of enzyme linked receptor
A
Receptor tyrosine-kinases (RTKs)
5
Q
what are RTKs?
A
the most common type of enzyme linked receptor
6
Q
how do kinase linked receptors exist and until when?
A
in an inactive state until they bind to signalling molecules
7
Q
when do kinase linked receptors stop existing in an inactive state?
A
when bound to signalling molecules
8
Q
what happens to inactive RTKs?
A
the tyrosine residues become phosphorylated by activated kinase domains
9
Q
what happens as phosphorylation of tyrosine residues in RTKs happens?
A
monomers come together to form a dimer
10
Q
why is it important that kinase residues in RTKs become phosphorylated?
A
phosphorylation of kinase residues provides a point of binding for extracellular signalling proteins
11
Q
what provides a point of binding for extracellular signalling proteins?
A
phosphorylation of kinase residues
12
Q
what happens when RTKs bind to proteins?
A
it produces downstream signalling pathways
13
Q
stages before an RTK can cause downstream signalling
A
tyrosine residues phosphorylated –> docking sites for intracellular signalling proteins –> downstream signalling
14
Q
examples of RTKs
A
insulin receptor
EGF receptor
VEGF receptor
IGF receptor
15
Q
what do RTKs tend to regulate?
A
transcription and translation
16
Q
due to RTKs regulating transcription and translation what does this effect?
A
DNA synthesis and cell survival, growth and proliferation
17
Q
which RTK signalling pathways are frequently mutated in cancer?
A
MAPkinase and PI3 kinase
18
Q
what happens in terms of RTKs when cancer cells become mutated?
A
can effect the level of expression of kinase signalling pathways
19
Q
biologics
A
antibody based drugs
20
Q
what do biologics bind to?
A
surface molecules like RTKs
21
Q
what is breast cancer caused by and what is done about this?
A
a rise in one type of RTK and so there’s an antibody in a drug to block this receptor
22
Q
what do RTKs have synergy with?
A
G-protein coupled receptors
23
Q
what’s the only type of receptor that isn’t membrane bound?
A
nuclear receptors
24
Q
stages that take place with nuclear receptors
A
hormone/agonist enters cell
interacts with IC nuclear receptor in cytosol or nucleus
NR/drug complex (drug-receptor complex) moves to nucleus
drug-receptor complex interacts with DNA to alter gene transciption
altered protein synthesis
25
what enters the cell to interact with an intracellular receptor protein (nuclear receptors)?
small hydrophobic signal molecule
26
what does a signal molecule bind to in the nucleus or cytosol (nuclear receptors)?
intracellular receptor protein
27
what are nuclear receptors in cytosol called?
cytosolic
28
what are the two types of nuclear receptors?
cytosolic
nuclear
29
example of cytosolic nuclear receptors
steroid receptors
30
example of nuclear receptors
thyroid receptors
31
examples of things that bind to nuclear receptors
endogenous hormones (e.g - corticosterone, aldosterone)
synthetic analogues (e.g - dexamethasone (steroid anti-inflammatory), anabolic steroids
32
where do nuclear receptors exist?
some in the nucleus, some in cytosol
33
what are anabolic steroids used for?
muscle growth
34
how do nuclear receptors work?
small hydrophobic signal molecule gets across the cell membrane by attaching to carrier proteins that deposit them where target cells are
35
are there a wide variety of nuclear receptors for drugs to bind to?
yes
36
type of drug targets
GPCRs
channel-linked receptors
enzymes
transport protein drug targets
37
what are enzymes?
proteins that catalyse chemical reactions, the conversion of substrate(s) to product(s)
38
what do enzymes catalyse?
chemical reactions where substrates are converted into products
39
are enzymes destroyed in chemical reactions? what does this mean?
no, they can be used over and over again
40
what do enzymes take us from and to?
substrates to products
41
modes of drugs inhibiting enzymes
competitive
false substrate
non-competitive (allosteric)
42
explain how competitive drugs inhibit enzymes
mimics the substrate, but not converted
43
explain how false substrate drugs inhibit enzymes
mimics the substrate, converted to abnormal product
44
explain how non competitive drugs inhibit enzymes
binds to allosteric site to alter activity of enzyme towards substrate
45
how can drugs reduce the amount of substrates enzymes convert into product?
by chemically resembling substrates and competitively inhibiting the substrate
46
which drugs mimic substrates for enzymes and are not converted and which which are converted to abnormal product?
competitive - not converted
false substrate - converted to abnormal product
47
what happens when non-competitive drugs bind to allosteric sites in enzymes?
alter the activity of enzyme towards substrate
47
where do non-competitive drugs bind to an enzyme?
to allosteric site
48
what are the two possible scenarios following a drug inhibiting an enzyme?
reversible
irreversible
49
explain reversable changes caused by drugs inhibiting enzymes
high levels of substrate overcome inhibition, if competitive (Km increases, Vmax is unaltered)
50
explain irreversible changes caused by drugs inhibiting enzymes
binds very tightly or covalently modifies the enzyme, long lasting clinical effect
51
what will happen eventually in a reversable inhibition of an enzyme with a drug?
eventually substrate will overcome the inhibition of a reversible enzyme inhibitor
52
what do all modes of inhibition by a drug on an enzyme lead to?
normal reaction blocked
53
well known examples of enzyme inhibitors
acetyl salicylic acid (aspirin)
ibuprofen
54
aspirin
acetyl salicylic acid
55
acetyl salicylic acid
aspirin
56
what does aspirin do at low doses?
anti thrombotic drug
57
what does aspirin do at high doses?
pain killer
58
when is aspirin an anti thrombotic drug?
at low doses
59
when is aspirin a pain killer?
at high doses
60
mechanism of action of aspirin
irreversible (covalent) inactivation of COX-1 and COX-2 by acetylation of enzyme
61
how does aspirin inactive COX 1 and 2?
by acetylation of the enzyme
62
what type of inactivation is irreversible?
covalent
63
what is aspirin an inhibitor of?
COX
64
how does aspirin inhibit COX 1 and 2 enzymes?
covalently
65
what is COX 1 involved in?
TxA2 synthesis in platelets, which amplifies platelet function
66
what are platelets involved in?
blood clotting
67
explain how aspirin behaves as an anti-thrombotic drug
thromboxane A2 (TxA2) is involved in the synthesis of platelets - aspirin is an anti-thrombotic drug and so at low levels, aspirin reduces the levels of TxA2
68
what is involved in the synthesis of platelets?
thromboxane A2 (TxA2)
69
what produces mediators that cause pain and fever and inflammation?
arachidonic acid
70
what does arachidonic acid do?
produces mediators that cause pain and fever and inflammation (what aspirin is used against)
71
how does aspirin act as a pain killer at high concentrations?
aspirin inhibits all of the inhibitors produces by arachidonic acid at high concentrations
72
what does COX 2 do?
involved in the synthesis of prostanoids which induce inflammation, pain and fever
73
what synthesises prostanoids which induce inflammation, pain and fever?
COX 2
74
what do prostanoids do?
induce inflammation, pain and fever (synthesised by COX 2)
75
difference between aspirin and ibuprofen
aspirin --> irreversible
ibuprofen --> reversible
76
what does ibuprofen do?
pain killer
reduces inflammation and temperature
77
mechanism of action of ibuprofen
competitive reversible inhibitor of COX 1 and COX 2
78
how does ibuprofen act as a pain killer?
by covalently inhibiting COX 2 which is involved in the synthesis of prostanoids which induce inflammation, pain and fever
79
what are enzymes important for in terms of drugs?
important as drug targets but also in producing drugs
80
pro drugs
drugs that require metabolism to work
81
drugs that require metabolism to work
pro drugs
82
up to which point do pro-drugs not work?
until they're metabolised by an enzyme, they don't work
83
how do pro-drugs start to work?
enzymes product an active metabolite which acts as a drug
84
what are enzymes also involves in apart from being drug targets?
also involved in the conversion of pro drugs from an inactive to an active form
85
examples of enzymes being involved in the conversion of pro drugs from an inactive to an active form
cortisone --> hydrocortisone (anti-inflammatory)
clopidogrel --> active metabolite (inhibits platelet aggregation)
86
what do concentration gradients result from?
the unequal distribution of ions between intracellular fluid and extracellular fluid
87
what are concentration gradients maintained by in cell biology?
the cell membrane
88
what does the cell membrane form around cells?
an impermeable barrier around all cells
89
what does the cell membrane allow to happen and why?
allows concentration gradients to exist between the inside and outside of cells since it forms an impermeable barrier around all cells
90
how come ionic concentration gradients can be maintained within a cell?
by having a lipophilic membrane that won't let charged molecules through, it allows cells to maintain their ionic concentration gradients
91
what does the lipophilic membrane around cells not let through?
charged molecules
92
what does the phospholipid bilayer not allow the passive transport (diffusion) of across the membrane?
charged particles or large polar molecules across the membrane
93
what does the phospholipid bilayer allow the passive transport (diffusion) of across the membrane?
gases (O2, CO2)
small polar molecules (H2O, EtOH)
lipid-soluble molecules (e.g - cortisol, benzene)
94
why do cells maintain different concentration gradients of ions?
osmosis
cell signalling
95
what do cells use to maintain concentration gradients?
transporters and ion channels
96
do transporters use passive or active transport?
both
97
passive transport
doesn't require energy - going down concentration gradients
98
active transport
requires energy (ATP) - ging against concentration gradients
99
what do transporters and ion channels allow cells to do?
to control their intracellular environment
100
two types of passive transport
channel-mediated
transporter-mediated
101
what needs to happen when transport with transporters occurs?
the molecule needs to bind first
102
what do molecules need to bind to first before transport can occur?
transporters
103
what happens during transporter mediated passive transport?
the transporter actually binds the molecule even though there's still a concentration gradient
104
types of passive transport
channel or transporter mediated
105
what happens when a molecule binds to a transporter?
it causes conformational changes in the transporter in order for it to transport the moleule
106
explain channel-mediated passive transport
ion channels that allow molecules to easily pass down through concentration gradient
107
what does active transport use?
a transporter
108
what are steroids an example of?
lipophilic molecules
109
properties of transporters
multipass transmembrane proteins
bind transported molecules
wide variety of molecules transported by transporters
undergo a series of conformational changes to transfer bound molecule
involved in passive or active transport
slower than ion channels
movement of ions can occur down or against their concentration gradients
110
how do transporters transfer bound molecules?
by undergoing a series of conformational changes
111
what type of transport are transporters involved in?
passive or active
112
are transporters or ion channels faster at transporting?
ion channels are faster
113
how do ions move using transporters?
down or against their concentration gradients
114
explain how glucose is transported across a cell
glucose gets across the cell by binding to a glucose transporter and when it binds, there's a conformational change in the transporter, which allows glucose to flip from the outside to the inside of the cell and then be released into the cell
115
types of transporter
uniport
symport
antiport
116
what type of transporter is a glucose transporter?
glucose transporter
117
uniport transporter
moves one type of molecule across the cell membrane
118
moves one type of molecule across the cell membrane
uniport transporter
119
symport transporter
moves two types of molecule across the cell
membrane in the same direction
uses the energy provided by the molecule moving down the concentration gradient to power the other molecule to move against its concentration gradient
120
moves two types of molecule across the cell
membrane in the same direction
uses the energy provided by the molecule moving down the concentration gradient to power the other molecule to move against its concentration gradient
symport transporter
121
antiport transporter
one molecule moves one way and the other molecule moves the other way at the same time
(the other may be moving against its concentration gradient or with)
122
one molecule moves one way and the other molecule moves the other way at the same time
(the other may be moving against its concentration gradient or with)
antiport transporter
123
what are transporters important for?
maintaining membrane potential and electrochemical gradients
124
what are important for maintaining membrane potentials and electrochemical gradients?
transporters
125
how are cells charged compared to the outside of the cell?
relatively negatively charged
126
how do cells maintain their negative charges?
by using transporters that maintain ion gradients
127
what can cells maintain by using transporters that maintain ion gradients?
negative charges
128
what is essential to maintaining ion gradients?
active transport
129
what is active transport essential for?
maintaining ion gradients
130
name two transporters that are essential in maintaining ion gradients
Na+/K+ ATPase
Na+/Ca2+ exchanger
131
what type of transporter is Na+/K+ ATPase? explain
antiport (K+ in, Na+ out)
132
what type of transporter is a Na+/Ca2+ exchanger? explain
antiport, but this time is passive since molecules are moving down their concentration gradients
133
explain the importance of a Na+/Ca2+ exchanger
Ca2+ is an important regulator and is essential for cells to work properly
134
give two examples of things that maintaining ion gradients is important for
muscle contraction
synaptic neurochemical release
135
what is important for muscle contraction and synaptic neurochemical release?
maintaining ion gradients
136
what is proof that maintaining ion gradients is importnat?
it accounts for 1/3 of total energy expenditure
137
what accounts for 1/3 of total energy expendicture?
maintaining ion gradients
138
name an active ingredient found in fox gloves
digoxin
139
what is digoxin?
an active ingredient found in fox gloves
140
what was digoxin used for?
an 18th century cure for dropsy (congestive heart failure)
141
what was used as an 18th century cure for dropsy?
digoxin
142
why isn't digoxin used to treat dropsy anymore?
it's been superceded by newer more selective drugs since there's lots of side effects to using digoxin
143
explain how digoxin works
digoxin blocks Na+/K+ ATPase transporter
increase in intracellular Na+
decrease in electrochemical gradient Na+
decrease in Ca2+ extrusion from cell (since the second transporter doesn't work as effectively)
increased Ca2+ in cell (less exiting via transporter)
increased concentration of Ca2+ in cardiac cells allows cells to contract more frequently
= digoxin is good in treating cardiac insufficiency
144
what is digoxin used to treat?
cardiac insufficiency/fibrillation/congestive heart failure
145
what do serotonin transporters do?
bring serotonin back into the cell
146
what type of transporter is a serotonin transporter? explain
symport that takes sodium and serotonin at the same time
147
explain how antidepressant drugs work
serotonin transporters are blocked by classes of antidepressant drugs to increase serotonin levels to improve mood
148
what are antidepressant drugs essentially?
drugs that stop serotonin transporters from working (block them) to increase serotonin levels to improve mood
149
what do antidepressant drugs cause a rise in and how?
synaptic serotonin levels by blocking transporters for therapeutic benefit
150
what rises when antidepressant drugs are used?
synaptic serotonin levels
151
what do ion channels do?
rush molecules across the concentration gradients at high speed
152
what do ion channels and transporters allow cells to do?
control their intracellular environment
153
properties of ion channels
small pores in the cell membrane formed by proteins
do not bind transported molecules
specificity determined by size and charge
open/closed conformations
voltage or ligand gated
very fast
movement of ions only occurs down their concentration gradients
154
do ion channels bind transported molecules like transporters do?
no
155
what is the specificity of ion channels determined by?
size and charge
156
two types of ion channels
voltage or ligand gated
157
how is a voltage gated ion channel opened?
change in electrochemical gradient to open
158
how is a ligand gated ion channel opened?
ligand/chemical binds to the channel to open them
159
how fast are ion channels?
very fast in terms of how quickly ions come through
>10^7 ions/sec cf transporters 10^2-3 molecules/sec
160
why is it important to maintain concentration gradients inside and outside of a cell?
since the movement of ions through ion channels only occurs down their concentration gradients
161
since the movement of ions only occurs down their concentration gradients, what's it important to happen?
that concentration gradients inside and outside of the cell are maintained
162
example of a voltage-gated ion channel
voltage-gated Na+ and Ca2+ channels
163
what are Na+ and Ca2+ channels examples of?
voltage gated channels
164
example of a ligand gated ion channel
nicotinic AChR
(Na+ channel)
165
what is a nicotininc AChR (Na+ channel) an example of?
a ligand gated ion channel
166
explain how nicotinic (Na+) ion channels work
acetylcholine binds to ligand gated channel to allow Na+ through
change in voltage (depolarisation of cell) to open Na+ and Ca2+ channels
Na+ required for muscle contraction
167
other way of describing change in voltage
depolarisation of cell
168
depolarisation of cell
change in voltage
169
what is Na+ required for?
muscle contraction
170
what is required for muscle contraction?
Na+
171
what type of voltage gated channels are there in the neuromuscular junction?
Na+ and Ca2+
172
what do the vesicles contain at the neuromuscular junction?
acetylcholine
173
give an example of where ion channels are important
neuromuscular junction
174
what is maintained along the axon membrane when no nerve impulse is being transported along the axon?
resting potential
175
potential difference across the axon membrane during a resting potential
-70mV
176
explain how a resting potential is maintained
by active transport: sodium-potassium pump pumps 3Na+ out of the axoplasm and only 2 k+ in. Also the axon membrane is highly permeable to K+ and they leak out by fascilitated diffusion through open channels. the outward movement of positive ions means the outside of the axon membrane is positive relative to the inside. the membrane is polarised. the atp needed to maintain a resting potential is produced by the numerous mitochondria presnent in the axoplasm of the axon.
177
what does the sodium-potassium pump do in order to maintain a resting potential?
pumps 3 Na+ sodium ions out of the axon for every 2 potassium ions that is pumps in. this is active transport which requires energy in the form of atp.
178
explain the action potential
nerve impulses are caused by a rapid change in the permeability of the neurone membrane to K+ and Na+
sodium ion channels in the membrane open; Na+ flood into the axon down their concentration gradient
potential across the membrane changes from -70mV (resting potential) to +40mV (action potential) - the membrane is said to be depolarised
around a millisecond after the sodium ion channels close, the potassium ion channels are open and K+ flood out of the axon. this repolarises the membrane.
an excess of K+ leave the axon before the Na+/k+ pump restores the resting potential. this is known as the refractory period during which no further action potentials can occur.
179
describe synaptic transmission
down nerves, there are a series of voltage-gated Na+ channels
change in voltage = channels will open
electrical signal down neurones
each sodium channel open in turn to get an electrical current running down the nerve cells = propagation of action potential
when a nerve impulse (Action potential) arrives at a synaptic end bulb, voltage-dependent calcium channels in the membrane open and calcium ions diffuse rapidly into the end bulb down their concentration gradient
synaptic vesicles, containing neurotransmitter (e.g - acetylcholine) move towards and fuse with the pre-synaptic membrane. the contents of the vesicles are released into the synaptic cleft by exocytosis.
the neurotransmitter diffuses across the synaptic cleft and binds to a receptor (ligand gated ion channel - a transmembrane protein) in the post-synaptic membrane
sodium ion channels in the post synaptic membrane open and sodium ions diffuse into the post-synaptic neurone causing depolarisation
if the threshold potential is reached, an action potential is initiated in the post synaptic neurone = sodium rushed in, which is required for muscle contraction
180
what does tubocurarine chloride interfere with?
the neuromuscular junction
181
give an example of something that intereferes with the neuromuscular junction
tubocurarine chloride
182
where does Tubocurarine chloride naturally occur?
from the bark of the S. American plant Chondrodendron tomentosum
183
what is Tubocurarine chloride used for?
source of arrow poison by S. American Natives to hunt animals
first skeletal muscle relaxant (stops muscle contraction)
used in surgery/reduces muscle damage
blocks the nicotinic acetylcholine receptor
184
what type of cells recognise changes in glucose levels?
beta cells in pancreas
185
where are beta cells found?
pancreas
186
what happens when beta cells in pancreas recognise changes in glucose levels?
pancreas can release insulin so that glucose can be taken up by cells
187
what can happen once the pancreas has released insulin?
glucose can be taken up by cells
188
what type of cells do people with type 1 diabetes not have?
beta cells in pancreas
189
what does insulin release involve?
transporters or ion channels
190
explain the stages of insulin release
1. glucose moves down its concentration gradient and enters the cell
2. glucose used in glycolysis and respiration = increase in ATP in beta cells in pancreas
3. ATP binds to an ATP-sensitive K+ channel
4. this closes the channel which causes the beta pancreatic cell to have a rise in intracellular potassium
5. this rise causes the voltage-gated Ca2+ channels to fire off = influx in Ca2+
6. rise in intracellular Ca2+ needed for the release of insulin
191
explain how drugs can be used to treat type 2 diabetes
can block the processes involved in insulin release with drugs. block ATP-sensitive K+ channels to cause an increase in insulin release
192
treatment for type 1 vs type 2 diabetes
1 = inject insulin
2 = drugs to cause more insulin release
193
why do we treat type 1 and 2 of diabetes differently?
type 1 = don't have beta cells at all (=inject insulin)
type 2 = have the cells, they just don't work properly so can use drugs to cause more insulin release
