DM Extra Notes Flashcards
Selections are?
Type I transmembrane glycoproteins with an N-terminal Ca2+ depending carbohydrate recognising lectin domain
What two phenomena affect leukocyte rolling?
To blood exerting a forward force pushing the cell forward but also a torque (about the cell centre) which rotates the cell like a wheel along the vessel wall. These are hydrodynamic drag acting on the rolling cell
What balances hydrodynamic drag?
Rapid formation and dissociation of p-selectin and PGSL1 bonds at the centre and rear of the rolling cell
Maximum Sheer stress is?
Shear stress acting near the blood vessel wall. Shear stress is 0 at the centre of the vessels
Four ways neutrophils can roll at high shear stress?
1 deformable cells undergo flattening at high sheer stress increasing the size of the cell footprint and reducing the hydrodynamic drag experienced
2 selectin ligand binds behave as catch bonds at small detachment bonds and tend to become stronger with increasing force
3 neutrophils rolling at high sheer dress have been shown to form 3-4 membrane tethers which can extreme up to 16μm behind the cell footprint
4 an autonomous adhesive structure called a sling is formed by leukocytes at high shear stress. Slings enable rolling by contributing to forces balancing the hydrodynamic drag acting on the rolling cell
The α chain of an integrins has what conserved amino acids on its IC tail and what is it used for? What is the β chain equivalent?
α chain is GFFKR conserved from salt bridge mediated interaction with the β chain. Mutations of GFFKR lead to constitutive activation of the integrin.
β chain and 2 NPXY/F motifs also crucial for salt bridge interacting
What is outside in signalling?
Interaction of integrins with their ligands which evokes additional internal signals of cell polarity, survival and proliferation which further strengthens the adhesion and regulates cell motility
What’s inside out signalling
Chemokine a bind to their receptions and trigger surface molecular on leukocytes promoting IC signals including PLC and activation of small GTPases and alteration of contacts with actin/ talin binding proteins which can result in rapid conformational changes or integrin clustering. Activated integrins have high affinity and/or high avidity towards their ligands of the Ig family
Role of rap GTPases in integrin signalling?
They are activated downstream of chemokine signalling and lead to LFA-1 and α4 integrin dependent adhesion
Constitutive active Rap1 leads to unregulated LFA-1 activation
Chemokine a are a what of integrin activation?
Agonist
How are integrins/ leukocyte adhesion molecules implicated in epilepsy?
Convulsive agents ie kainic acid cause up regulated adhesion molecules which mediate leukocyte adhesion. Leukocyte migration comprmises endothelial barrier function. If the BBB is compromised this can cause plasma leakage into the brain parenchyma and result in neuronal cells being exposed to K+ ions and albumin leading to neuronal hyperactivity and reduced threshold for seizures
What contributes to lymphocyte exit from the lymph node?
What mediated lymphocyte trafficking in the lymphatics?
S1P1
Macrophage mannose receptor and CLEVER1
What chemokine a are attracted to:
IL8
RANTES, MIP-1α, MIP-1β
IP-10
IL8 - CXCR1/2 on neutrophils
RANTES, MIP-1α, MIP-1β - CXCR1/5 on immature DC and CCR5 on NK cell
IP-10 - CCR5 on NK cell and CCR3 on activated T cell
What are galectins?
Endogenous lectins that can bind carbohydrates in a calcium independent fashion
15 galactins exist
Galectins bind to N-acetyllactosamine (disaccharide) with what affinity?
Individual SUs with low affinity
Repeating polylactoamines affinity increases 100 fold
