Lipids and Cell Membranes 2 Flashcards
How do lipids participate in cell-cell communication mechanisms?
by giving rise to intracellular second messengers.
They also serve as precursors for compounds that are released from cells and act on other cell types, called eicosanoids – inflammatory mediators.
What are the 6. steps of cell-cell communication?
- Synthesis of signal.
- Release of the signaling molecule by the signaling cell: exocytosis, diffusion, cell-cell contact.
- Transport of the signal to the target cell.
- Detection of the signal by a specific receptor protein
- A change in cellular metabolism, function or development triggered by the receptor-signal complex
- Removal of the signal or desensitisation
How can signalling by extracellular molecules be classified in animals?
Long range
Short range
What are long range extracellular signalling molecule types?
Endocrine: hormone released by endocrine cell and carried in bloodstream to distant target cells
Neurotransmission
What are short range extracellular signalling molecule types?
Paracrine: signaling molecules only affect target
cells in close proximity to secreting cells
Autocrine: cells respond to substances that they themselves release
Membrane-bound proteins can interact to signal
Provide an example of neurotransmission signalling
Example: Breathing – the phrenic and thoracic nerves send impulses from the brain to the diaphragm
Provide an example of paracrine signalling
Examples: somatostatin release by pancreas cells acts locally. Neurotransmission can also be considered to be a type of paracrine signaling.
Provide an example of autocrine signalling
Example: Some neurotransmitters and growth factors bind to the cells that release them.
Provide an example of membrane-bound proteins that can interact to signal
Example: signalling by T cells in the immune system
Provide an example of multiple types of signalling occurring simultaneously
Example: insulin released from pancreatic β-cells acts in an autocrine, a paracrine and an endocrine manner
Why is signal transduction important?
Many signalling molecules that affect cell activity or function do not enter cells
What is signal transduction?
Signal molecules that don’t pass through the cell membrane act on membrane-bound receptors that control the production of intracellular chemicals (second messengers).
These mediate cell activity.
Exception is lipid soluble signalling molecules (bind intracellular receptors)
What are the two types of receptors that signalling molecules bind to?
Cell-surface receptors - (hydrophilic signalling molecule)
Intracellular receptors - (hydrophobic signalling molecule)
How long do ligand gated ion channels (inotropic receptors) take to cause cellular effects when activated?
Milliseconds
How long do G-protein-coupled receptors (metabotropic) take to cause cellular effects when activated?
Seconds
How long do kinase-linked receptors take to cause cellular effects when activated?
Hours
How long do nuclear receptors take to cause cellular effects when activated?
Hours
What is the general rule of thumb when determining the length of time it takes for a signalling molecule to cause action in relation to their intermediate functions intracellularly?
If the cell surface receptor protein causes an intracellular signalling pathway that directly causes altered protein function it gonna be fast (< sec to mins)
If the intracellular signalling pathway instead acts on the nucleus to cause altered protein synthesis then it gonna be slow (mins to hrs)
Either way its gonna cause altered cytoplasmic machinery and thus altered cell behaviour
How do lipid soluble molecules act on a cell?
They leave their binding protein in the plasma and enter the cell through the phospholipid bilayer
They then bind to a specific receptor in the nucleus/cytoplasm to form a messenger-receptor complex that binds to DNA
This causes a protein synthesis that leads to altered cell response
Provide an example of the action of a lipid soluble molecule?
Cortisol enters the cell through the membrane and bonds with an intracellular receptor protein
This causes a conformational change that activates the receptor protein
The activated receptor-cortisol complex moves into the nucleus
The activated receptor-cortisol complex then binds to regulatory region of target gene and activates transcription
Describe the inositol phospholipid signalling pathway
Phosphatidylinositol 4,5-bisphosphate (PIP2) is a phospholipid found in the lipid bilayer.
It is the substrate of the enzyme phospholipase C (PLC).
PLC liberates two signalling molecules from PIP2; inositol 1,4,5 trisphosphate (IP3) and diacyglycerol (DAG).
What role does calcium have in cellular pathways?
calcium activates cellular pathways
How does calcium activate cellular pathways?
Calcium concentration transiently increases in the cell in response to IP3 release
Calcium binds to proteins to regulate their function
Example: Ca2+/Calmodulin - activates proteins/enzymes through direct interaction
(e.g. myosin light chain kinase, which regulates smooth muscle contraction)
Whats a kinase do?
Adds phosphates as an enzyme
What are some substrates of protein kinase C (PKC) ?
tumour suppressor p53 (transcription factor) → prevents tumour formation
CaV 1.2 (calcium channel) → heart muscle contraction
IKKα (cytokine) → B cell activation (immune function)
What are eicosanoids (prostanoids)?
Inflammatory mediators
Describe the area of action of eicosanoids (prostanoids)
The eicosanoids are considered “local hormones.”
- They have specific effects on target cells close to their site of formation (autocrine/paracrine).
- They are rapidly degraded, so they are not transported to distal sites within the body.
What are some principal eicosanoids (prostanoids)?
PROSTAGLANDINS, THROMBOXANES & LEUKOTRIENES.
What is the etymology of eicosanoids (prostanoids)?
Word eicosanoid derived from EICOSA indicating 20 carbon atom backbone and ENOIC meaning double bonds.
What is the main source of eicosanoids (prostanoids)?
Main source of eicosanoids is arachidonic acid, a 20 carbon unsaturated fatty acid containing 4 double bonds (20:4).
What is the initial and rate limiting step in eicosanoid (prostanoid) biosynthesis?
The initial and rate-limiting step in eicosanoid synthesis is the liberation of arachidonic acid by phospholipase A2 (PLA2)
How is PLA2 activated?
by a variety of receptor-mediated signals
What can arachidonic acid be metabolised by in eicosanoid biosynthesis?
(a) cyclo-oxygenase and peroxidase to give prostaglandins and thromboxanes
(b) lipoxygenases to give leukotrienes.
What do prostaglandins do?
Vasoconstriction/dilation (redness, swelling and heat)
Inhibit/promote platelet aggregation
Effects depend upon receptor (e.g. EP1 receptor → vasoconstriction; EP2 receptor → vasodilation)
Inflammatory response, thermoregulation (fever) and pain
Where can prostaglandins be found?
They are synthesised in all tissues and cell types
What do thromboxanes do?
Short-lived (autocrine/paracrine action)
Thromboxane A2 (TXA2) has prothrombotic properties
Stimulate platelet aggregation
Vasoconstrictor
Where can thromboxanes be found?
Synthesised in platelets (clotting)
What do leukotrienes do?
Some contain the amino acid cysteine in their structure (anaphylactic shock)
Immune response
Heavily implicated in asthma and allergy
Where can leukotrienes be found?
“Leuko” because they are synthesised in white blood cells and “trienes” because they contain a conjugated triene system of double bonds.
What do platelet-activating factors do?
Platelet aggregation
Vasoconstriction
Inflammation
Immune response (also anaphylaxis)
How are platelet-activating factors formed?
Not strictly an “eicosanoid”
By-product of arachidonic acid liberation
Synthesised in leukocytes (platelets, neutrophils, basophils)
Also synthesised by injured tissue (e.g. endothelial cells)
What are NSAIDs?
Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and derivatives of ibuprofen, inhibit cyclooxygenases.
What do NSAIDs do?
They inhibit formation of prostaglandins involved in fever, pain, & inflammation.
They inhibit blood clotting by blocking thromboxane formation in blood platelets.
Give an example of a NSAID?
Ibuprofen and related compounds block the hydrophobic channel by which arachidonate enters the cyclooxygenase active site.
What does aspirin do?
Aspirin acetylates a serine hydroxyl group near the active site, preventing arachidonate binding.
The inhibition by aspirin is irreversible.
However, in most body cells re-synthesis of Cox-1 would restore cyclooxygenase activity.
Describe the action of aspirin as an anticoagulant
Thromboxane A2 stimulates blood platelet aggregation, essential to the role of platelets in blood clotting.
Many people take a daily aspirin for its anti-clotting effect, attributed to inhibition of thromboxane formation (via COX-1 inhibition) in blood platelets.
This effect of aspirin is long-lived because platelets lack a nucleus and do not make new enzyme.
How does cell calcium concentration increase?
Calcium concentration transiently increases in the cell in response to IP3 release
