Lipids in Cell Membranes Flashcards
What are some of the roles of phospholipids in the cell ?
- Make up lipid bilayer
- Participate in cell-cell communication mechanisms by giving rise to intracellular second messengers.
- serve as precursors for compounds that are released from cells and act on other cell types
What are phospholipids precursors of ?
Eicosanoids (inflammatory mediators)
What are the 6 steps of cell-to-cell communication ?
1) Synthesis of signal
2) Release of the signaling molecule by the signaling cell: exocytosis, diffusion, cell-cell contact
3) Transport of the signal to the target cell
4) Detection of the signal by a specific receptor protein
5) Change in cellular metabolism, function or development triggered by the receptor-signal complex
6) Removal of the signal or desensitisation
Do signals act at short or long range ?
Both
In animals, signaling by extracellular molecules can be classified into different types, what are these types ? Give that an example for each.
LONG RANGE
1) Endocrine (Hormones): released by endocrine gland and carried in bloodstream to distal target cells
E.g. Follicle-stimulating hormone released from the pituitary acts upon the ovary
2) Neurotransmission: transmission of nerve impulses across a synapse (between an axon and dendrite or between an axon and muscle cell) through a neurotransmitter
E.g. Breathing – the phrenic and thoracic nerves send impulses from the brain to the diaphragm
SHORT RANGE
1) Paracrine: signaling molecules only affect target cells in close proximity to secreting cells
E.g. Somatostatin release by pancreas cells acts locally. Neurotransmission can also be considered to be a type of paracrine signaling.
2) Autocrine: cells respond to substances that they themselves release
E.g. Some neurotransmitters and growth factors bind to the cells that release them.
3) Signalling by plasma membrane-attached proteins: Membrane-bound proteins can interact to signal
E.g. signalling by T cells in the immune system
Give an example of a mechanism which utilises many of the aforementioned cell signalling methods simultaneously.
Insulin is released from pancreatic β-cells acts in an autocrine (acts on β-cells), a paracrine (acts on alpha cells) and an endocrine (acts on liver/muscle/adipose tissue) manner.
Do signalling molecules enter cells ?
Many do not but lipid soluble signalling molecules (hydrophobic) do
How do signalling molecules which do not enter cells work ?
They act on extracellular membrane-bound receptors that control the production of intracellular chemicals (second messengers).
Where do the signalling molecules which do enter cells bind ?
Bind intracellular receptors
Give a few examples of types of intracellular and extracellular receptors, along with their time scale and a few examples of specific ones.
EXTRACELLULAR
-Ligand gated ion channels (ionotropic): Milliseconds.
E.g. Nicotinic ACh receptor
-G-protein coupled receptors (metabotropic): Seconds.
E.g. Muscarinic ACh receptor
-Kinase-linked receptors: Hours
E.g. Cytokine receptors
INTRACELLULAR
-Nuclear receptors: Hours.
E.g. Oestrogen receptor
Why do the receptors which take hours do so ?
Because they require transcription and gene synthesis
What are the two main paths taken inside the cell when extracellular signalling molecules bind to the receptor, to alter cell behaviour ?
FAST (seconds to mins)
Signalling molecule binds to receptor –> Altered Protein Function –> Altered Cytoplasmic Machinery –> Altered Cell Behaviour
SLOW (mins to hrs)
Signalling molecule binds to receptor –> Altered Protein Synthesis (through nucleus, requires transcription to take place) –> Altered Cytoplasmic Machinery –> Altered Cell Behaviour
Give examples of lipid-soluble molecules. Since they are hydrophobic, how do they remain in the plasma before entering the cell ?
Steroid hormones (cortisol, testosterone) Carried in plasma using a plasma protein
Is the intracellular receptor always in the nucleus ?
No
Describe the way in which cortisol alters cell function.
1) Carried in blood by plasma protein
2) Penetrates into the cell
3) Binds to intracellular receptor in cytosol
4) Activated receptor-cortisol complex moves into nucleus
5) Activated receptor-cortisol complex binds to regulatory region of target gene and activates transcription
What are the main molecules involved in Inositol phospholipid signalling pathway ? Where is the receptor found ?
Phosphatidylinositol 4,5-bisphosphate (PIP2), phospholipid receptor in lipid bilayer
Enzyme phospholipase C (PLC) (PIPI2 is its substrate)
What is the effect of PLC on PIP2 ?
PLC liberates two signalling molecules from PIP2; inositol 1,4,5 trisphosphate (IP3) and diacyglycerol (DAG)
Describe the Inositol phospholipid signalling pathway.
G-Protein linked receptor receives signal molecules –> G protein alpha subunit is activated –> Active protein switches on enzyme which cleaves IP3 from DAG –> IP3 binds to ER Calcium channels –> Ca2+ channels open and Calcium concentrations in cytosol increase –> Binding of DAG and Calcium to Protein Kinase C (enzyme) activates it –> PKC phosphorylates proteins and hence modifies their functions
Other than PKC, state an example where Calcium binds to proteins to regulate their function.
Ca2+/Calmodulin - activates proteins/enzymes through direct interaction
(e.g. myosin light chain kinase, which regulates smooth muscle contraction)
Give examples of substrates for PKC, and the actions that each one performs.
Tumour suppressor p53 (transcription factor) → prevents tumour formation
CaV 1.2 (calcium channel) → heart muscle contraction
IKKα (cytokine) → B cell activation (immune function)
Once signal transduction has taken place, where does IP3 go ?
IP3 is recycled back to the membrane as PIP2 (Phosphatidylinositol turnover)
What are Eicosanoids (prostanoids) ?
They are Inflammatory mediators.
Which type of signalling molecule are Eicosanoids considered to be ? Why ?
LOCAL HORMONES, because:
- Have specific effects on target cells close to their site of formation (autocrine/paracrine)
- Are rapidly degraded, so they are not transported to distal sites within the body
What are the main eicosanoids ?
PROSTAGLANDINS, THROMBOXANES & LEUKOTRIENES.
What is the chemical structure of eicosanoids ?
20 carbon atom backbone with double bonds
Which molecule is the main source of eicosanoids ? What is the structure of this molecule ?
Arachidonic acid, a 20 carbon unsaturated fatty acid containing 4 double bonds (20:4)
Describe the steps of Eicosanoid Biosynthesis.
1) PLA2 is activated by a variety of receptor-mediated signals, including serotonin receptors, glutamate receptor 1, some cytokine receptors, increased Ca2+
2) The liberation of arachidonic acid from the initial phospholipid (yielding also Platelet-Activating-Factor) by phospholipase A2 (PLA2)
3) Arachidonic Acid metabolised by one of two classes of enzymes:
a) cyclo-oxygenase and peroxidase (converted to endoperoxidases first) to give prostaglandins (including prostacyclin) and thromboxanes
(b) lipoxygenases (converted into hydroperoxy and hydroxy FAs first) to give leukotrienes.
What is the RLS in Eicosanoid Biosynthesis ?
Liberation of arachidonic acid by phospholipase A2 (PLA2)
Where are Prostaglandins synthesised ?
Synthesised in all tissues and cell types
What are the main effects of Prostaglandins ?
1) Vasoconstriction/dilation (redness, swelling and heat). Effects depend upon receptor (e.g. EP1 receptor → vasoconstriction; EP2 receptor → vasodilation)
2) Inhibit/promote platelet aggregation
3) Inflammatory response, thermoregulation (fever) and pain
Where are Thromboxanes synthesised ?
Synthesised in platelets
What kind of signalling molecule are Thromboxanes ?
Short-lived (autocrine/paracrine)
What are the main effects of Thromboxanes ?
1) Thromboxane A2 (TXA2) has prothrombotic properties
I.e. Stimulate platelet aggregation + Vasoconstrictor
How may TXA2 be inactivated ?
By being hydrated (TXA2 + H2O –> TXB2), where TXB2 is inactive
Where are Leukotrienes synthesised ?
Synthesised in WBCs
What is a defining characteristic of their chemical structure ?
Contain a conjugated triene system of double bonds.
What are the main effects of Leukotrienes ?
1) Immune response
2) Heavily implicated in asthma and allergy
3) May induce anaphylactic shock (because some contain the amino acid cysteine in their structure )
Are Platelet-activating factors eicosanoids ?
Not strictly, they are a by-product of arachidonic acid liberation.
Where are PAFs synthesised ?
In leukocytes (platelets, neutrophils, basophils) and by injured tissue (e.g. endothelial cells)
What are the main effects of PAFs ?
- Platelet aggregation
- Vasoconstriction
- Inflammation
- Immune response (also anaphylaxis)
State examples of Non-steroidal anti-inflammatory drugs (NSAIDs).
Aspirin and derivatives of ibuprofen
What is the function of non-steroidal anti-inflammatory drugs (NSAIDs) ?
Inhibit cyclooxygenases. Consequently,
- inhibit formation of prostaglandins (involved in fever, pain and inflammation)
- inhibit formation of thromboxane (in blood platelets, thus inhibiting blood clots)
How does Ibuprofen and related compounds inhibit cyclooxygenases ?
They block the hydrophobic channel by which arachidonate enters the cyclooxygenase active site.
Is aspirine inhibition of cyclooxygenases reversible ?
No, irreversible
Given that aspirine inhibition of cyclooxygenases is irreversible, how could one restore cyclooxygenase activity ?
Through re-synthesis of re-synthesis of Cox-1
Explain the anti-coagulant properties of aspirine.
Because it inhibits thromboxane formation (via COX-1 inhibition) in blood platelets.
In the context of anti-coagulation, are the effects of aspirine long or short-lived ? Why ?
Long-lived because platelets lack a nucleus and do not make new enzyme.
Identify the type of drug, mechanism, and use of the following drugs:
- Ibuprofen
- Aspirine
IBUPROFEN
- Type: NSAID
- Mechanism: COX1 and COX2 inhibition
- Use: Pain relief
ASPIRIN
- Type: NSAID
- Mechanism: COX1 inhibition
- Use: pain relief; anticoagulation
How does aspirine inhibit cyclooxygenases ?
Acetylates a serine hydroxyl group near the active site, preventing arachidonate binding.
