Cell signalling and receptors Flashcards

1
Q

What are the types of signals that can be produced?

A
  1. Mechanical
  2. Biochemical
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2
Q

For a biochemical signal, what is required?

A

A ligand and a receptor

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3
Q

What is a signal ligand?

A

a small molecule that forms a complex with a macromolecule typically a receptor protein that results in a conformational change in the receptor that then generates a signal

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4
Q

Tell me 3 different forms of signal

A
  1. Contact- dependent signals
  2. Cell-matrix signals
  3. soluble signals; Autocrine, Paracrine, Endocrine
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5
Q

Tell me about Contact- dependent signals (juxtacrine)

A
  • require interaction between membrane molecules on two cells
  • cells must be touching
  • signals are transmitted through cell membranes via protein or lipid componenets integral to the membrane of the emitting cells
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6
Q

Tell me about Cell-matrix signals

Provide some examples of them

A
  • insoluble signalling molecules

examples;

a. Mesenchymal cells (neurons, muscle cells, fibroblast) are surrounded by a matrix

b. Chondrocyte cell surrounded by matrix (cartilage)

c. Cell-matrix interactions can be organised at focal contacts

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7
Q

Where is an epithelial cells matrix found?

A

Only on one side

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8
Q

Tell me about Autocrine signals

Provide some examples

A

They are secreted and affect the target cell itself via its own receptors

Examples;

1. Interleukin-1; a cytokine released by macrophages. effects neighbouring cells and the secreting cell “activating them”

2. Interleukin-2; is released by T lymphocytes on meeting an antigen and causes them to proliferate

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9
Q

Tell me about intracrine signals

provide an example

A

They are produced by and stay within target cells (a version of autocrine signalling)

Examples

  1. adipose tissue
  2. some steroid hormones have their receptors in the cell so can act as intracrine (and paracrine and endocrine signals)
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10
Q

Tell me about Paracrine signals

Provide some examples

A

These signals target cells in the vicinity of the emitting cell

They are localised signals

Examples

  1. Immune cells; neurotransmitters at synapses
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11
Q

Tell me some local mediators of paracrine signals which are released into the interstitual fluid

A
  1. Histamine
  2. TGFß
  3. Growth factors
  4. cytokines
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12
Q

Are chemical synapses- neuronal signals paracrine signals?

A

yes

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13
Q

Tell me about Endocrine signals

Provide an examples

A

They target distant cells by producing hormones that travel through the circulation to reach all parts of the body

Examples

  1. adrenalin
  2. thyroid stimulating hormone
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14
Q

Tell me some hormones and their concentration at low concentration in the blood/interstitual fluid

A

Thyroxine 0.09-20 pg/ml

Oestrodiol 20-400 pg/ml

Prolactin 3-15 ng/ml

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15
Q

What is 1pg in grams…

1 Pg = … g

A

1 pg= 1x10-12 g

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16
Q

Tell me about the affinity of hormone receptor binding

A

Has a far greater affinity (low Kd) compared to others

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17
Q

What are hormone receptors part of?

A

amplification cascades

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18
Q

Tell me some chemical classification of external messengers and examples for each

A

Gases: NO, CO, H2S, CO2.

Nucleic Acids: ATP, ADP and adenosine.

Fatty acid derivatives: Eicosanoid e.g. prostaglandins, thromboxanes, leukotrienes, PAFs.

Cholesterol derivatives: steroids

Amino acids and derivatives: glycine, glutamate, thyroid hormones, catecholamines- e.g. adrenaline

Peptides: e.g. TRH

Proteins: e.g. Insulin

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19
Q

What are gases produced by ?

A

specific enzymatic pathways

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20
Q

Tell me about the solubility of gases and what this allows them to do/ not to do

A

They are highly soluble in water and lipids

Can cross plasma membrane

can’t be stored

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21
Q

Are gases only made when they are needed ?

A

yes

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22
Q

What type of local effects do gases produce?

A

Paracrine and autocrine effects

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23
Q

What type of responses do they produce?

A

Generally, cause vasodilation and may have immunological effects

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24
Q

Tell me what nucleic acids function as paracrine signalling molecules

A

The purinergic nucleotides ATP/ADP and their nucleoside adenosine

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25
What do nucleic acids specifically have and what is this associated with?
Have specific cell surface receptors Have G proten associated with them
26
What happens with nucleic acids during cellular stress (e.g. ischemia /reperfusion or inflammation) ?
multiple cell types release ATP into the extracellular space
27
What type of effects do nucleic acids have?
Vasodilation, neural effects (in development), innate immune changes e.g. inflammatory cytokine release, fever
28
As the fatty acid derivatives are polar, what does this mean for their transport?
They don't rapidly cross the cell membrane so have receptors
29
Tell me some examples of polar fatty acid derivatives
PAFs and Eicosanoids e.g. prostaglandins, thromboxanes, leukotrienes
30
What type of signals do fatty acid derivatives produce? How are they produced?
Paracrine signals Produced through modification and release of lipids in the plasma membrane Eicosanoids – arachidonic acid Platelet activating factor-phosphorylcholines
31
Tell me some roles of fatty acid derivatives
Regulate immune responses, inflammation (vascular permeability), pain reactions, vasoconstriction/ dilation and clotting
32
Cholesterol derivatives are hormones that are transported by the circulatory system to target distant organs. Give some examples of these hormones
**Sex (gonadal/ placental) steroids**: Oestrogens, Progesterone’s, Testosterone. **Adrenal steroids**: Mineralocorticoids (aldosterone) Glucocorticoids (cortisol) **Vitamin D**: (can’t make this, but its structure is that of a steroid so classed as this)
33
Are cholesterol derivatives produced on demand ?
yes
34
Cholesterol aren't very water soluble so how are they transported?
May have a carrier in the plasma
35
Where are cholesterol derivatives receptors found and why?
Main receptors are inside the cell and not at the membrane as they are lipid soluble molecules so readily cross the membrane
36
What are amino acid derivative produced by ?
exocytosis
37
Are amino acid derivative relativelt lipid soluble?
no, they are lipid insoluble
38
Tell me some amino acid, paracine, neurotransmitters and whether they are excitatory or inhibitory
**Glutamate, Aspartate:** excitatory **Glycine:** inhibitory
39
Amino acid derivative are active **Biogenic amines,** how are they produced?
by the decarboxylation of amino acids
40
Give 3 examples of amino acid derivatives?
1. **Histamine** 2. **GABA** 3. **Serotonin**
41
Tell me what amino acid **Histamine** is derived from and its Histamines role?
Derived from **Histidine** (paracrine) role: immune responses, vasodilation, acid secretion in GI tract, neurotransmitter
42
Tell me what **GABA (gamma-aminobutyric acid)** is derived from and GABA's role ?
Derived from; **glutamate** (paracrine) role; inhibitory neurotransmitter
43
Tell me what **serotonin** is derived from, and serotonins role?
dervided from; **tryptophan** role; neurotransmitter, vasodilation
44
When are **Catecholamines** produced and give 3 examples and their roles?
produced after **tyrosine decarboxylation** Examples and their roles; 1. **Dopamine;** Neurotransmitter 2. **Noradrenaline;** Neurotransmitter 3. **Adrenaline;** Hormones and neurotransmitter
45
Tell me another tyrosine modification
conjugated/ iodinated hormones
46
When decarboxylating an amino acid, what is the enzyme?
_Histidine_ **Decarboxylate** _(The name of what enzyme was decarboxylated)_
47
What is the largest class of signalling molecules?
Peptides and proteins
48
What is the range in sizes of peptides and proteins?
from 3 AA (e.g. TRH= Glu-His-Pro-(N) to growth hormone e.g. GH~ 200 AA
49
Peptides and proteins are not soluble in lipids, what term is used to describe this?
Lipophobic
50
Tell me 3 types of signal molecules?
1. **Lipophilic (hydrophobic) molecules** 2. **Hydrophilic molecules** 3. **Tyroid hormones**
51
Tell me about **Lipophilic (hydrophobic) molecules** and give some examples
like to be in lipid not aq environment e.g. Steroids (cortisol) and Gases (NO). Can enter the cells so the receptors can be anywhere, often within the cytosol. (sometimes found in nucleus)
52
Tell me about **hydrophilic molecules** and give some examples
e.g. Amines (serotonin), Amino Acids (Glycine), Peptides (ACTH) and Proteins (Insulin). Can’t cross the plasma membrane so receptors at the cell surface.
53
Tell me about **thyroid hormone**
* are Hydrophobic * have **a carrier at the cell surface** to bring the ligand into the cell * have receptors in the cytoplasm * An amino acid derivative (produced from tyrosine) * An exception
54
Compare **intracellular signal receptors** and **cell membrane receptors**
55
Define **signal transduction?**
How chemical or physical signals are transmitter through a cell as a series of molecular events
56
How are chnages elicited in signal transduction and what does this cause?
The changes elicited by ligand binding to a receptor which gives rise to a **signalling cascase**, a chnage of biochemical events- a signalling pathway
57
signalling pathways may interact with one another to form networks, which allow coordinated cellular responses. Give some responses?
* changes in the transcription or translation of genes. * Don’t act in isolation * post-translational and conformational changes in proteins. * changes in protein location. * changes in ion concentration. * alter cell growth * proliferation * metabolism * movement * secretion
58
What are **First messengers?**
signalling molecules (hormones/ paracrine/ autocrine agents) that reach the cell from the extracellular fluid and bind to their specific receptors.
59
What are **second messengers?**
substances that relays message from the plasma membrane to the cytoplasm to trigger a response.
60
What do cell surface receptors need?
second messengers
61
Examples of second messengers...
62
Give 3 examples of lipophilic signalling?
* **NO (nitric oxide)** * **Steroids** * **Tyroxine**
63
Give examples of plasma membrane receptors for hydrophilic signalling?
* **Ligand-gated ion channels** (e.g. nicotinic acetylcholine receptor) * **G-protein-linked receptors** (β-adrenergic receptor) * **Enzyme-linked receptors** (growth factor receptors)
64
What type of signal molecules is **NO ?**
A Non-polar local mediator
65
Why cant NO be retained in vesicle stores?
Its lipophilic
66
What happens to NO directly after synthesis?
It immediately leaves its site of synthesis and diffuses into all adjacent cells
67
What cells does NO only affect?
Those with an NO receptor
68
Why is NO known as a local mediator
its broken down quickly so doesnt get very far after synthesis
69
What is NO produced from?
Arginine
70
What does the production of NO depend on?
NO synthase
71
What are the 3 forms of NO synthase (NOS) and where is each found/ used?
1. **eNOS** - blood vessel endothelial cells 2. **nNOS** - neuronal cells 3. **iNOS** - inducible isoform occurring in cells of the immune system
72
NO produced by eNOS helps control what?
control the diameter of blood vessel's hence and blood pressure
73
For eNOS, what is the endothelia stimulated by?
* Histamine * Acetylcholine (from nerve endings) * Increased sheer flow
74
When NO diffuses into the smooth muscle, what effects does it cause?
* Vasodilation * Reduced blood pressure
75
In NO signalling, whats the target for NO?
**Guanylate cyclase** NO binds to active site of guanylate cyclase and activates it
76
In NO signalling, **cGMP** is produced, what does this act as and what does it cause?
This acts as a second messenger and causes relaxation
77
Tell me the steps to how cyclic cGMP causes muscle relaxation?
* Blocks Ca2+ entry into the cell by phosphorylating Ca2+ channels, decreasing intracellular calcium concentrations inhibiting myosin-actin interactions. * Phosphorylates and activates K+ channels, which leads to hyperpolarization and relaxation. * Phosphorylates and activates myosin light chain phosphatase (phosphatase removes the phosphate), this phosphorylates myosin chains and causes smooth muscle relaxation.
78
When NO is rapidly oxidised to NO3-, what does this mean?
* rapid spontaneous breakdown (a short-lived signal) * Guanylate cyclase is inactivated
79
what is cGMP converted to GMP by? What happens in the bonds for this reaction to happen?
cGMP is converted to GMP by the **enzyme phosphodiesterase** (11 isoforms) - breaks the phosphodiesterase bond with the 3’OH ribose
80
How does Viagra work?
Sildenafil (Viagra) blocks the action of phosphodiesterase 5, prolonging the relaxation of blood vessel smooth muscle in the penis - treatment of impotence
81
What is the role of **phosphatases?**
Phosphorylated downstream enzymes converted back to original form by phosphatases
82
What type of hormones are steroids?
hydrophobic
83
What are steroids synthesised from?
synthesised from cholesterol and are immediately released
84
Why can't steroids be stored?
They are hydrophobic
85
Where are steroids released into and where do they travel to ?
They are released into the blood and are carried into tissues. they then readily diffuse into cells where they bind to cytoplasmic receptors
86
When steroids bind to their receptors, what sites does it unmask?
* **DNA binding sites** * **nuclear localisation sites**
87
How is the steroid signal removed?
metabolism of the steroid
88
Steroid release process
89
As seen below, steroids have very similar structures, why are the effects so different?
Even though structure Is similar, the effects are very different because the receptors are very specific.
90
What is the testosterone receptor also known as?
The **androgen receptor NR3C4**
91
What does the mutation of the testosterone receptor lead to?
it prevents or reduces testosterone signalling despite the presence of the hormone Male individuals (XY) with mutated androgen (testosterone) receptors are incapable of signal transduction thus are biologically male, but phenotypically immature male or female
92
Tell me about thyroxine signalling?
* The thyroid hormones can’t cross the cell membrane but have transporters to bring them into the cell. * They then diffuse into the nucleus * Once in the nucleus they act in a similar manner as steroids – however their receptors are already in the nucleus
93
What drives the movement of Ions across the plasma membrane?
* concentration gradient * electrochemical gradient
94
When the ligand gated ion channel is opened what does this cause?
A change in ion concentration at the inner side of the membrane fast and change potential difference (Na+/ K+) - this is very localised and quick
95
when some ions bind to proteins, what can it cause?
* conformational changes * signal transduction
96
Tell me some facts about signalling?
* **Rapid**- milliseconds * **Localised**- only region close to opening of the channel (unless amplified) * can be **quickly reveted** to normal
97
Give some examples of some FAST ligand-gated ion channels Out of those listed, which bind and activate different types of receptors?
**Nicotinic acetylcholine receptor** **Glutamate receptor** **Seratonin (5HT) receptor** **GABA receptor** Glycine receptor Extracellular ATP receptor **(bind and activate different types of receptors)** **Important: Most of these ligands can bind to other types of receptor - G-protein linked receptors exist for all these ligands except glycine and ATP.**
98
What can the **Nicotinic Acetylcholine receptor** bind?
Nicotine and Ach
99
What does the nicotinic acetylcholine receptor belong to and what is this?
Belongs to the superfamily of ligand-gated ion channels (thought to have evolved from a common ancestor)
100
The nicotinic acetylcholine receptor is a pentamer made of what differing subunits?
**α2βγδ or α2β3**
101
What binds to the muscarinic receptor?
only Ach
102
Tell me about the structure of the nicotinic acetylcholine receptor?
* 5 polypeptides α2βγδ or α2β3. * Each polypeptide contains 4 alpha helices. * 3 are mainly hydrophobic and contact the lipid membrane. * 1 of these (M2) is an amphipathic helix and lines the pore (regions of hydrophobic and hydrophilic). If M2 are lined up together you can form a channel which allows cold water to pass through but not hot * The 5 amphipathic helices produce a channel across the membrane * The α subunits have the acetylcholine binding regions. * Conformation changes on binding of 2 acetylcholine molecules.
103
When Ach binds to the Nicotinic acetylcholine receptor, what happens?
the helices rotate which pulls the charged residues from the pore which opens it
104
When ligands bind to the Nicotinic acetylcholine receptor what happens?
causes transient (fast) opening of the channel to allow the **cations** to enter (Na+, Ca2+, K+) It is non-selective but is particularly permeable for Na+ and K+. However, it is **mainly Na+ ions that pass.**
105
Why can't anions enter the nicotinic acetylcholine receptor?
The size and polarity of the pore blocks larger and negatively charged ions
106
Tell me the about the concentrations of K+, Na+ and Cl- intracelluarly and extracelluarly?
* The membrane potential of excitable cells is around –70mV (negative in). * The effect of opening the Nicotinic receptor is predominantly an inflow of Na ions due to the electrochemical gradient.
107
when Ach receptor opens, why does the membrane become depolarised?
As Na+ ions enter the cell
108
Tell me about generation of an action potential?
* When the acetylcholine receptors are opened the membrane becomes depolarised as Na+ ions enterthe cell. * If sufficient are opened, adjacent voltage-gated sodium channels sense the depolarisation of the membrane. * These transiently open causing a wave of depolarisation (this is the action potential) to sweep across the cell membrane triggering events in distant parts of the cell
109
Tell me what happens when the following channels are opened? 1. **Na+** 2. **K+** 3. **Cl-**
1. **Opening Na+ channels** will depolarise the cell as the membrane potential and sodium gradient result in Na+ entering the cell. 2. **Opening K+ channels** will hyperpolarise the cell as K+ leaves the cell. 3. **Opening Cl- channels** will hyperpolarise the cell as Cl- enter
110
Name some other ligand gated ion channels
* **Serotonin (5-HT3) receptors** (cation channel) * **Ionotropic glutamate recepto**r (cation channel) * **GABAA receptor** (chloride channel) * **Glycine** (chloride channel) When chloride channels open the membrane hyperpolarises, this counteracts the excitability of the membrane caused by the binding of ligands that open cation channels
111
Name the 3 major classes of receptors and give examples for each
1. **Ligand-gated ion channels** (e.g., nicotinic acetylcholine receptor) 2. **G-protein-linked receptors** (β-adrenergic receptor) 3. **Enzyme-linked receptors** (growth factor receptors)
112
What kind of structure do G-protein linked receptors have?
They all have a 7 pass structure (cross the membrane 7 times) Big loop between 5 and 6
113
Tell me some roles of G-protein linked receptors
114
What type of complex is the G-protein complex? Why is it called this?
It is a **Trimeric complex** contains; * alpha * beta * gamma
115
Where are all the parts of the G complex attached to?
The inner side of the plasma membrane
116
What does the alpha unit of a G complex contain?
A **GTP/GDP binding site** and **GTPase activity**
117
When is the alpha subunit active/ inactive?
When **GTP** is bound, an **active** signalling complex is formed When converted to **GDP** (or no nucleotide is bound) it is **inactive**
118
Whats the equation for the formation of GDP and what the enzyme involved in this? How long does the reaction take?
119
What does GDP help to reform?
The trimeric complex
120
Are there large and small G proteins?
yes
121
What are the large G proteins also known as?
αβγ
122
Tell me the function/ importance of the large and small G proteins ?
**Large proteins:** Link to the inner plasma membrane and associate with receptors **Small proteins:** importatn for downstream events in signal transduction and wont be discussed in course
123
Can active signalling complexes be active for a large range of time?
yes
124
In the inactive atate what is **GPCR** bound to?
A **Heterotrimeric G protein complex**
125
When a ligand binds to the extracellular surface of the GPCR what does this cause?
It results in a conformational change in the receptor that is transmitted to the bound Galpha subunit it causes the Galpha subunit to release GDP and exchange it for GTP
126
When GDP is released what does this trigger?
The dissociation of Galpha subunit from the **GßY** dimer and from the receptor- both are **active complexes** results in two active signalling complexes
127
What do G proteins dissociate into when activated?
2 signalling proteins Galpha and GßY
128
How many different forms are there of; * Galpha * Gß * Gy
20 different forms of **Galpha ** 5 different forms of **Gß** 13 different forms of **Gy**
129
What do the different forms of G protein subunits show their differences in?
* expression patterns * receptor binding * effects produced in the cell
130
What does the differences between the G protein subunits mean?
* specificity to their signals
131
What are the different type of Galpha subunits are there? What do each activate/ inactivate?
1. **Gas:** activates adenylyl cyclase 2. **Gai:** Inactivates adenylyl cyclase 3. **Gaq:** Activates Phospholipase C
132
When the Gas activates adenylyl cyclase, what receptor does it bind to?
ß- adrenergic receptor
133
What is the role of **Adenylate cyclase?**
It converts ATP to the second messenger **cyclic AMP (cAMP)**
134
Whats the role of **cAMP?**
Activates a protein kinase called **protein kinase A (PKA)** By binding to the regulatory subunits of the proteins which causes the release of the active catalytic subunits
135
Whats the amplification step is Gas process?
ATP --\> cAMP
136
Write the reaction for ATP--\> cAMP and the enzymes/ products involved
137
Can cAMP signalling have fast and slow effects?
yes
138
Write the equation which demonstrates the rise of cAMP concentration following the application of the signalling molecules of serotonin
139
Name a ligands that activates adenylyl cyclase
adrenaline
140
In some prostglandin receptor, what can Gai inactivate?
the membrane bound enzyme adenylyl cyclase
141
What does the subunit Gai reduce?
The second messenger cAMP
142
Whats happens when a hormone such as ADH binds to Gaq?
E.g. Antidiuretic Hormone can bind to a G-protein-linked receptor. In this case the activated Gα-subunit switches on the enzyme phospholipase C which cleaves the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) (a phospholipid component of the bilayer). Forms 2 second messenger’s inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)
143
How does Ach activate 2 signalling pathways?
by activating phospholipase C
144
What does **inositol 1,4,5-triphosphate (IP3)** act as? How does it do this?
A second messenger How: * IP3 releases Ca2+ from stores in the endoplasmic reticulum. * cytoplasmic **[Ca2+] rises from 0.1 to 10 μM (x100)** * Ca2+ + DAG activate **protein kinase C.** * Protein kinase C activates a number of protein targets, including proteins involved in transcription (turning on the expression of particular proteins) * Inactivated by converting to metabolites in the cell
145
How does Calcium activate **Calmodulin dependent kinase (CaM-kinase)?**
It binds to the protein **calmodulin**
146
whats the role of **CaM kinase?**
Regulating the activity of many proteins including some involved in transcription
147
What are the 2 main classes of enzyme-linked receptors?
1. Receptor tyrosine kinases 2. Receptor serine/ threonine kinases
148
Whats the largest class of enzyme-linked receptor? Give an example?
Largest class are the **receptor tyrosine kinases** (about 60 different receptors) e.g. insulin or fibroblast growth factor (FGF) receptor, HER2
149
Give some examples for the **receptor serine/ threonine kinase** Whats its role?
bone morphogenetic protein (BMP) TGFß Main role is laying down extracellular matrix
150
State the ways in which signals are turned off?
1. **Spontaneous breakdown** 2. **Enzymatic breakdown** 3. **Reuptake** 4. **Receptor/ligand internalisation**
151
Tell me about Spontaneous breakdown, using the example of NO
* NO is very labile (a free radical with an unpaired electron) and is converted to NO3- quickly and needs no catabolising enzyme * Hence it can’t move far from its site of production and has very local effects * Spontaneous and doesn’t require an enzyme * Localised effects
152
Tell me the two forms of enzymatic breakdown that could occur?
* **Acetyl cholinesterase** * **Proteases**
153
Tell me about Acetyl cholinesterase break down
Acetyl Cholinesterase **breaks down acetylcholine at the synapse**. The enzyme is at high concentration (mostly membrane bound) and so there is only very local effect at the synapse which is short acting
154
Tell me about Protease break down?
cleave peptide/ protein hormones (insulin, glucagon etc), these are often at lower concentrations and so produce longer term effects
155
Tell me about reuptake and some examples
Many neurotransmitters are transferred back into the secreting cell e.g. GABA, glycine, serotonin
156
Tell me about receptor/ligand internalisation and some examples
Some ligands and their receptor are brought into the cell following binding via. Endocytosis Ligand to be recycled or broken down e.g. somatostatin and Luteinizing hormone.
157
Breakdown/ uptake pathways are targets for pharmaceutical agents. Name 2 agents?
* **Neostigmine** * **Fluoxetine**
158
Tell me the role of **Neostigmine** and what its used to treat
blocks acetylcholine esterase and so increases the effectiveness of acetylcholine used to treat myasthenia gravis (autoimmune disease where body acts against the Ach receptors)
159
Tell me about **Fluoxetine** and what its used to treat
Another name for it is Prozac blocks serotonin uptake at the synapse, inhibits serotonin transporter used to treat depression as the ligand is retained at the synapse for longer.