Lipid signalling

Membrane functions

barrier, signal transduction, transport, setting up gradients, maintaining cell shape and rigidity, compartmentalisation and specialisation

Membrane structure

4nm thick, hydrophobic and asymmetric bilayer made of lipids and proteins. Held together by weak non covalent interactions

Hydrophobic effect

water molecules interact with non-H bonding groups so fewer H bonds are exchanged, creating a more solid state with decreased entropy due to more stable H bonds forming

Glycerophospholipids

two fatty acids linked to glycerol with a phosphate head group, eg phosphatidylcholine

Sphingolipids

Lipids with a sphingoid base backbone. Associate with cholesterol/proteins and each other

sphingoid

aliphatic amino alcohol

glycerolipids

1+ fatty acid chain attached to glycerol. Lipid storage, signalling functions or intermediates in glycerophospholipid synthesis

What are the three types of membrane lipid?

phospholipids, glycolipids and cholesterol

Phospholipids

Membrane lipids that can spontaneously form vesicles due to their amphipathic nature

Why is asymmetry in the bilayer important?

signalling, apoptosis, blood clot formation, protein targeting etc

Phosphatidylinositol

key signalling molecule located on the inner membrane leaflet

Apoptosis and membrane asymmetry

phosphatidylserine (normally inner leaflet) is exposed on the surface of dying cells by flippase, signalling for macrophage recognition.

What happens when platelets are activated by blood vessel injury?

Lipids in membrane scrambled to expose phosphatidylserine (cytoplasmic leaflet normally) on surface where it acts as cofactor in converting coagulation proteins to a clot

what happens when membrane lipids are hydrolysed by phospholipases?

they are removed from the membrane potentially altering membrane structure, integrity and fluidity

Phospholipase A2

releases arachidonic acid, precursor for inflammatory mediators like prostaglandins, thromboxanes and leukotrienes

Prostaglandins

potent, short lived molecules which act on GPCRs to exert a paracrine or autocrine effect

COX1

converts arachidonic acid to prostaglandin H2

What is prostaglandin H2 converted into?

TXA2, prostaglandins or prostacyclin via attached synthase enzymes

prostaglandin functions

platelet aggregation, spinal neuron pain, smooth muscle constriction and inflammation

Thromboxane

vasoconstrictor/hypertensive agent that facilitates platelet aggregation. In balance with prostacyclin.

Leukotrienes

promote inflammation via endothelial cell adherance and mast cell chemokine production. Induce asthma

Endocannabinoid system (ECS)

neuromodulatory system of cannabinoid receptors, endogenous cannabinoids and enzymes which synthesise and degrade endocannabinoids

ECS disruptions

linked to schizophrenia and other conditions

similarities between 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamids (anandamide, AEA)

Both endogenous cannabinoids containing arachidonic acid and both synthesised from omega 6 polyunsaturated fatty acids

differences between 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide, AEA)

very different routes of synthesis and degradation in vivo, mediated by different enzymes

ECS receptors

CB1/2 (GPCRs which couple to Gi and Go classes), transient receptor potential channels and peroxisome proliferator activated receptors

Where are CB1 receptors found?

mainly presynaptic neurones in the CNS

Where are CB2 receptors found?

peripheral nervous system and immune cells

ECS functions

linked with appetite, metabolism, pain, inflammation, sleep, motor control and more

ECS and disease

involved in cancer, cardiovascular disease and neurodegenerative disease

CB1R as a drug target

mediates reward responses so could be targeted for mood/anxiety disorders

cannabimimetic drugs

• target ECS and its enzymes

• enhance bioactivity/activation or inhibit inactivation of endocannabinoids

rimonabant

inverse agonist of CB1 designed as an anti-obesity drug. Removed from market due to dramatic effects on mood

Phosphoinositides

minor class of phosphorylated lipids involved in signalling, intracellular trafficking and compartment/organelle identity

localisation of ptdins3P

endosomes

localisation of ptdins4P

ER, Golgi and secretory vesicles

localisation of ptdins(3,5)P2

multivesicular bodies/late endosome

localisation of ptdins(4,5)P2

membrane clathrin coated pits

PI3K

phosphoinositide involved in vesicle trafficking, glucose transport, chemotaxis and DNA synthesis

why can PI3Ks have many different effects in the same cell?

spatial and temporal regulation, and different effector proteins

Plechstrin homology domain

domain in some cytosolic proteins which selectively binds phosphorylated phosphatidylinositol derivatives eg PI3P

when is PIP3 generated by fat cells

in response to PDGF (localised clusters) and insulin (mass generation)

Lipid rafts

Specialised membrane regions enriched in sphingolipids and cholesterol, facilitating efficient signaling by recruiting specific proteins.