week 7 lipid signalliong Flashcards
What are bioactive lipids, and what types of biological functions do they regulate?
✅ Model Answer:
* Definition:
Bioactive lipids are lipid-derived molecules that function as signalling messengers, either extracellularly or intracellularly.
* Examples of Bioactive Lipids:
o Eicosanoids (e.g., prostaglandins, leukotrienes, thromboxanes)
o Endocannabinoids (e.g., anandamide, 2-AG)
o Lysophospholipids
o Sphingolipids
o Cholesterol derivatives
* Functions Regulated:
o Inflammation
o Development
o Neurogenesis
o Cognition
o Motor control
o Pain
o Feeding
o Cell proliferation, migration, apoptosis
✏️ Question 2:
List the major classes of bioactive lipids and briefly describe one example from each class.
✅ Model Answer:
* Eicosanoids:
o Derived from arachidonic acid.
o Example: Prostaglandins involved in inflammation and pain.
* Endocannabinoids:
o Lipid molecules that bind CB1/CB2 receptors.
o Example: Anandamide regulates synaptic transmission.
* Lysophospholipids:
o Products of phospholipid degradation.
o Example: Lysophosphatidic acid (LPA) regulates cell proliferation.
* Sphingolipids:
o Derived from sphingosine.
o Example: Sphingosine-1-phosphate (S1P) regulates immune responses.
* Cholesterol derivatives:
o Includes steroid hormones.
o Example: Glucocorticoids regulate metabolism and inflammation.
✏️ Question 3:
Which types of receptors do bioactive lipids typically activate? Give examples.
✅ Model Answer:
* G-Protein Coupled Receptors (GPCRs):
o LPA receptors (LPA1–3)
o S1P receptors (S1P1–5)
o Platelet activating factor (PAF) receptor
o Cannabinoid receptors (CB1, CB2)
o Prostaglandin receptors (9 types of eicosanoid receptors)
* Nuclear receptors:
o Steroid hormones bind intracellular receptors to regulate gene transcription (not focused on this lecture).
* Other receptors:
o Rhodopsin receptor (retinal derivative).
✏️ Question 4:
Describe how arachidonic acid is produced and its significance.
✅ Model Answer:
* Production:
o Derived from the diet (meat, eggs) or synthesized from linoleic acid.
o Released from membrane phospholipids by phospholipase A2.
* Significance:
o A key precursor for many signalling lipids including prostaglandins, leukotrienes, and endocannabinoids.
o Arachidonic acid is an omega-6 fatty acid, often linked to pro-inflammatory signalling.
✏️ Question 5:
What is the role of phospholipases in lipid signalling molecule production?
✅ Model Answer:
* Phospholipase A1 and A2:
o Release free fatty acids (e.g., arachidonic acid) by cleaving membrane phospholipids.
* Phospholipase C:
o Produces diacylglycerol (DAG) and inositol phosphates, involved in secondary messenger pathways.
* Phospholipase D:
o Removes head groups like choline to modify membrane phospholipids.
✏️ Question 6:
Identify the two main endocannabinoids and their general functions.
x
✅ Model Answer:
* Anandamide (AEA):
o Regulates synapse formation, neurogenesis.
o Influences cognition, motor control, feeding, and pain.
* 2-Arachidonoylglycerol (2-AG):
o Important for retrograde synaptic signalling.
* Both:
o Bind to CB1 (neuronal) and CB2 (immune) receptors.
o Act as modulators of neurotransmission.
Describe the biosynthetic pathway for anandamide and 2-AG.
✅ Model Answer:
* Anandamide:
o Synthesized from phosphatidylethanolamine by:
1. N-acyltransferase (adds arachidonic acid).
2. Phospholipase D (cleaves to release anandamide).
* 2-AG:
o Synthesized from phosphatidylinositol by:
1. Phospholipase C (produces DAG).
2. Diacylglycerol lipase (produces 2-AG).
What is the controversy regarding anandamide transport across membranes?
✅ Model Answer:
* Anandamide is amphipathic (soluble in both membranes and aqueous environments).
* Debate:
o Passive diffusion vs. specific transporter proteins (e.g., EMT).
* Cholesterol appears to influence anandamide membrane transport, but whether directly or indirectly remains unclear.
Describe the two main enzymes involved in the degradation of endocannabinoids.
✅ Model Answer:
* Fatty Acid Amide Hydrolase (FAAH):
o Breaks down anandamide into arachidonic acid and ethanolamine.
* Monoacylglycerol Lipase (MAGL):
o Degrades 2-AG into arachidonic acid and glycerol.
* Clinical Note:
o A Scottish woman with FAAH mutation showed pain insensitivity, no fear, faster wound healing.
How does CB1 receptor activation affect neuronal activity?
Model Answer:
* CB1 activation couples to Gi/o proteins:
o Inhibits adenylate cyclase → ↓ cAMP → ↓ PKA activity.
o Activates MAP kinase pathways (gene expression changes).
o Inhibits calcium channels → reduces neurotransmitter release.
o Activates potassium channels → hyperpolarizes neurons.
Describe the unusual process of discovering cannabinoid receptors.
✅ Model Answer:
* CB1 receptor was discovered by homology cloning.
* Identified through its similarity to other GPCRs.
* Found to be activated by ΔTHC (active ingredient in cannabis) before endogenous ligands were identified.
* Highlighted the existence of the endogenous endocannabinoid system.
Explain retrograde endocannabinoid signalling at synapses.
✅ Model Answer:
* Endocannabinoids are produced in the postsynaptic neuron.
* They diffuse back across the synapse to bind presynaptic CB1 receptors.
* Inhibits neurotransmitter release by:
o Blocking calcium influx.
o Activating potassium efflux.
* Acts as a negative feedback mechanism.
Differentiate between retrograde, non-retrograde, and neuron-astrocyte signalling by endocannabinoids.
✅ Model Answer:
* Retrograde:
o ECs released from postsynaptic neuron inhibit presynaptic neurotransmitter release.
* Non-retrograde:
o ECs act on postsynaptic CB1 or TRPV1 channels.
* Neuron-astrocyte:
o ECs stimulate astrocytes to release glutamate, modulating presynaptic activity.
What is short-term synaptic plasticity mediated by endocannabinoids?
✅ Model Answer:
* Rapid production of 2-AG following synaptic activation.
* Temporary suppression of neurotransmitter release.
* Example: Depolarization-induced suppression of excitation (DSE) at glutamatergic synapses.
What is long-term depression (LTD) mediated by endocannabinoids?
✅ Model Answer:
* Prolonged activation of CB1 receptors leads to:
o Sustained inhibition of neurotransmitter release.
o Synapse-specific weakening (either excitatory or inhibitory synapses).
* Important in learning and memory.
What is N-arachidonyl-glycine (NAGly), and how does it function?
✅ Model Answer:
* Endogenous lipid structurally related to anandamide.
* Inhibits glycine transporters (GlyT2).
* Provides analgesia in models of neuropathic pain.
* Problems:
o Low potency, rapid metabolism, non-specific actions.
What advantages does oleoyl-D-lysine have over NAGly?
✅ Model Answer:
* Much higher potency (~500x more potent than NAGly).
* Selective inhibition of GlyT2 without off-target effects.
* Provides strong analgesia in neuropathic pain models with minimal side effects.
List the main classes of bioactive lipids and provide an example of each.
✅ Model Answer:
* Eicosanoids:
o Derived from arachidonic acid.
o Example: Prostaglandins regulate inflammation and pain.
* Endocannabinoids:
o Lipid-derived modulators of neurotransmission.
o Example: Anandamide and 2-arachidonoylglycerol (2-AG).
* Lysophospholipids:
o Produced from phospholipid degradation.
o Example: Lysophosphatidic acid (LPA) promoting cell proliferation.
* Sphingolipids:
o Derived from sphingosine backbone.
o Example: Sphingosine-1-phosphate (S1P) regulating immune cell movement.
* Cholesterol derivatives (Steroids):
o Example: Glucocorticoids regulating metabolism and immune responses.
How are bioactive lipids typically generated in cells?
✅ Model Answer:
* General Pathway:
o Membrane phospholipids serve as the starting point.
o Phospholipases (A1, A2, C, D) cleave phospholipids to release precursors like arachidonic acid.
o Arachidonic acid can then be converted into various signalling molecules (eicosanoids, endocannabinoids).
* Specific Example:
o Phospholipase A2 releases arachidonic acid from the membrane → Cyclooxygenase (COX) converts it into prostaglandins.
* Endocannabinoid Example:
o Anandamide produced via enzymatic modification of phosphatidylethanolamine by N-acyltransferase and phospholipase D.
Which key enzymes are involved in the biosynthesis and breakdown of endocannabinoids, and where are they located?
✅ Model Answer:
* Biosynthesis Enzymes:
o Phospholipase C (produces DAG for 2-AG synthesis) – postsynaptic.
o Diacylglycerol lipase (DAGL) (converts DAG to 2-AG) – postsynaptic.
o N-acyltransferase and N-acylphosphatidylethanolamine phospholipase D (for anandamide synthesis) – postsynaptic.
* Breakdown Enzymes:
o Fatty Acid Amide Hydrolase (FAAH) – degrades anandamide – postsynaptic.
o Monoacylglycerol Lipase (MAGL) – degrades 2-AG – presynaptic.
* Transport:
o Anandamide membrane transporter (EMT) – present on both pre- and postsynaptic membranes (debated).
Describe how endocannabinoids like anandamide and 2-AG mediate their biological effects.
✅ Model Answer:
* Retrograde Signalling:
o Endocannabinoids are produced in postsynaptic neurons.
o They diffuse back to presynaptic terminals to bind CB1 receptors.
* Result:
o CB1 activation inhibits calcium influx and promotes potassium efflux in presynaptic cells.
o This reduces neurotransmitter release, modulating synaptic strength.
* Functions Regulated:
o Pain perception.
o Appetite.
o Cognition.
o Motor control.
* Additional Mechanisms:
o Non-retrograde signalling (on postsynaptic CB1 or TRPV1).
o Neuron-astrocyte signalling (stimulates gliotransmission via astrocytic CB1 receptors).
Explain how CB1 and CB2 receptors mediate cellular responses when activated.
✅ Model Answer:
* Receptor Type:
o Both CB1 and CB2 are Gi/o protein-coupled receptors.
* Signalling Cascade:
o Inhibits Adenylyl Cyclase (AC):
Reduces cAMP production → lowers PKA activity.
o Activates MAPK pathways:
Alters gene expression.
o Modulates Ion Channels:
Inhibits voltage-gated calcium channels.
Activates potassium channels.
Resulting in hyperpolarization and reduced neurotransmitter release.
* Distribution:
o CB1: Highly abundant in CNS (especially hippocampus, cerebellum, basal ganglia).
o CB2: Mostly in immune cells, regulating inflammatory responses.
