Lipids in cell membranes 2 Flashcards
What are the roles of phospholipids?
They 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 in other cell types called Eicosanoids
What are Eicosanoids?
Inflammatory mediators
What are the 6 steps involved in cell-cell communication?
- 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. A change in cellular metabolism, function or development triggered by the receptor-signal complex 6. Removal of the signal or desensitisation
What are the 2 ranges signals can be ?
Short or long-range
What are the 2 different types of long range cell to cell communication?
1). Endocrine: hormone released by endocrine celll and carried in the bloodstream to distal target cells E.g - FSH released from pituitary acts upon the ovary 2). Neurotransmission E.g - Breathing - the phrenic and thoracic nerves send impulses from the brain to the diaphragm
What are the 3 different types of short range cell to cell communication?
1). Paracrine: signalling 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 signalling 2). Autocrine: Cells respond to substances that they themselves release E.g - Some neurotransmitters and growth factors bind to cells that release them (like negative feedback) 3). Membrane-bound proteins: Can interact to signal by the plasma membrane attached proteins E.g - Signalling by T cells in the immune system
How do all of the different types of signalling interact with one another?
Multiple types of signalling can be occurring simultaneously E.g - Insulin released from pancreatic B-cells acts in an autocrine, a paracrine and endocrine manner
How do the majority of signalling molecules that affect cell activity or function work on the cell?
They do not enter the cells and act on membrane bound receptors that control the production of intracellular chemicals (second messengers) - Usually hydrophilic These mediate cell activity The exception is lipid soluble signalling molecules, they bind to intracellular receptors (usually hydrophobic)
How do Ligand-gated ion channels (ionotropic receptors) work?
The ligand binds to the receptor and the channel opens causing a Hyperpolarisation or depolarisation causing cellular effects This occurs in Milliseconds and an example is the Nicotinic ACh receptor
How do G-protein-coupled receptors (metabotropic) work?
Receptors are coupled to G-proteins and when the substate binds to the receptor the G-proteins can stimulate the ion channels to open them or activate enzymes to act as second messengers and complete different activities in the cell (E.g calcium release, protein phosphorylation) This occurs in seconds and an example is the Muscarinic ACh receptor
How do Kinase-linked receptors work?
The receptor/enzyme kinase is activated and can cause protein phosphorylation then gene transcription, resulting in protein synthesis causing cellular effects This occurs over hours and an example is the Cytokine receptors
How do nuclear receptors work?
Nuclear receptors often stimulate gene transcription in the nucleus which gives rise to new proteins which will give different cellular effects This occurs over hours and an example is the Oestrogen receptor
What is the time difference between pathways that do transcription in the nucleus and those that dont?
The pathways that do transcription in the nucleus are much slower and take minutes to hours than the ones that don’t which are fast and done in less than seconds to minutes
How are lipid soluble molecules transported inside cells?
They are bound by a carrier protein in the blood plasma as they are soluble. They detach from the binding protein and diffuse through the cell into the nucleus where they bind with a receptor and trigger transcription which causes a protein to be made and an altered cell function
How does cortisol work?
Cortisol is a lipid-soluble molecule which causes a conformational change and activates an intracellular receptor protein where the two bind to one another creating an activated receptor-cortisol complex which moves into the nucleus and binds to the regulatory region of the target gene to activate transcription.
What is Phosphatidylinositol 4,5-biphosphate (PIP2) and the enzyme phospholipase C (PLC) and their functions ?
- Phosphatidylinositol 4,5-biphosphate (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 triphosphate (IP3) and diacyglycerol (DAG)
What happens in the Inositol phospholipid signalling pathway?
- A signalling molecule activates a G-protein linked receptor which activates a G-protein subunit - This activates the enzyme phospholipase C which liberates two signalling molecules from Phosphatidylinositol 4,5-biphosphate (PIP2), a phospholipid found in the lipid bilayer - This creates inositol 1,4,5 triphosphate (IP3) and diacyglycerol (DAG) - The inositol 1,4,5 triphosphate (IP3) activates the Calcium channel on the endoplasmic reticulum causing a calcium influx inside the cell to activate PKC (Protein kinase C) and the binding of the diacyglycerol (DAG) also further activates the Protein kinase C (both substances are required to activate it)
How does Calcium activate cellular pathways and give an example?
Calcium concentration transiently increases in the cell in response to IP3 release Calcium binds to proteins to regulate their function Example; Calcium/Calmodulin activates proteins/enzymes through direct interaction (e.g - Myosin light chain kinase, which regulates smooth muscle contraction)
What kind of functions can an increased cellular level of calcium do?
- Exocytosis - Contraction - Metabolism - Gene transcription - Fertilisation - Proliferation - Hypertrophy
What happens once protein kinase C is activated and what are the outcomes of these?
Substrates for PKC’s include; - tumour suppressor P53 (transcription factor) -> prevents tumour formation - Ca(v) 1.2 (calcium channel) -> heart muscle contraction - IKKa (cytokine) -> B cell activation (immune function)
What happens after signal transduction occurs in the cycle ?
After signal transduction has taken place IP3 is recycled back to the membrane as PIP2
What are Eicosanoids considered as and what properties does this give them?
Eicosanoids are considered to be 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 the principle Eicosanoids (prostanoids)?
Prostaglandins, Thromboxanes and Leukotrienes
Where is the word Eicosanoid derived from?
The word Eicosanoid is derived from EICOSA indicating 20 carbon atom backbone and ENOIC meaning double bonds
What is the main source of Eicosanoids?
The main source of Eicosanoids is arachidonic acid, a 20 carbon unsaturated fatty acid containing 4 double bonds (20:4)
What is the initial rate and rate-limiting step in Eicosanoid synthesis controlled by?
The liberation of arachidonic acid by phospholipase A2 (PLA2)
What is PLA2 activated by?
PLA2 is activated by a variety of receptor-mediated signals (serotonin receptors, glutamate receptor 1, some cytokine receptors and an increase calcium concentration)
Draw the pathway of Eicosanoid biosynthesis?
Below
What can Arachidonic acid be metabolised by?
A). Cyclo-oxygenase and peroxides to give prostaglandins and thromboxjnes
B). Lipoxygenases to give Leukotrienes
What are the features of Prostaglandins?
Prostaglandins; - Synthesised in all tissues and cell types • Vasoconstriction/dilation (redness, swelling and heat) Inhibit/promote platelet aggregation • Effects depend upon receptor (e.g. EPI receptor -> vasoconstriction; EP2 receptor -> vasodilation) • Inflammatory response, thermoregulation (fever) and pain PG12 (prostacyclin)
What are the features of Thromboxanes?
Thromboxanes;
- Synthesised in platelets (clotting)
- Short-lived (autocrine/paracrine)
- Thromboxane A2 (TXA2) has prothrombotic properties
- Stimulate platelet aggregation
- Vasoconstrictor
What are the features of Leukotrienes?
Leukotrienes;
- “Leuko” because they are synthesised in white blood cells and “trienes” because they contain a conjugated triene system of double bonds.
- Some contain the amino acid cysteine in their structure (anaphylactic shock)
- Immune response
- Heavily implicated in asthma and allergy
What are the features of the Platelet-activating factor ?
Platelet-activating factor;
- 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)
- Platelet aggregation
- Vasoconstriction
- Inflammation
- Immune response (also anaphylaxis)
What are NSAIDS?
Non-steroidal anti-inflammatory drugs E.g - Asprin and derivatives of ibuprofen which inhibit cyclooxygenases
What are the roles of NSAIDS and how do they do this?
• They inhibit formation of prostaglandins involved in fever, pain, & inflammation. • They inhibit blood clotting by blocking thromboxane formation in blood platelets. Ibuprofen and related compounds block the hydrophobic channel by which arachidonate enters the cyclooxygenase active site.
How does Aspirin prevent arachidonate binding?
Aspirin acetylates (adds acetyl function group to) 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-I would restore cyclooxygenase activity.
How does Aspirin chemically work 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-I inhibition) in blood platelets. - This effect of aspirin is long-lived because platelets lack a nucleus and do not make new enzyme.
What are examples of anti-inflammatory drugs which target Eicosanoid pathways ? (Give the drug, type, mechanism and uses)
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