M&R Flashcards
What does amphipathic mean?
Containing both hydrophilic and hydrophobic moieties
Describe a phospholipid:
Polar head group with large FA chains - C16-18
Unsaturated C=C chains in cis formation with kink reducing phospholipid packing
Which phospholipid is the only one not based on glycerol?
Sphingomyelin
What is a glycolipid?
Sugar containing lipids
What is cholesterol?
a plasma membrane lipid that adds structure to the lipid bilayer
How do bilayers form in water?
Spontaneous due to the van der walls forces between the hydrophobic tails
What forces aid the bilayer formation?
Electrostatic and H-bond between hydrophobic moieties, interactions been hydrophilic groups and water
What movements can lipid molecules do in the bilayer?
Intra-chain motion
Fast axial rotation
Fast lateral diffusion
Flip-flop exchange
Examples of membrane proteins?
Enzymes, transporters, pumps, ion channels, receptors
What movements can membrane proteins do?
Conformational change
Rotational
Lateral
What movement do proteins not do in membranes?
flip-flop because of their large hydrophilic groups - it would take too much energy to pass through hydrophobic regions
Forces in peripheral membrane proteins?
Electrostatic and H-bonds
Removed by changes in pH and ionic strength
Forces in integral membrane proteins?
Hydrophobic regions in lipid bilayer.
Can’t be removed by changes to pH or ionic strength, - requires detergent to compete for non-polar interactions
What function do unsaturated fatty acids do?
kink in chain > reduces phospholipid packing > increasing membrane fluidity
What does cholesterol do?
H-bond to the FA chains
Reduces phospholipid packing > increasing membrane fluidity
Also reduces phospholipid chain motions > decrease membrane fluidity
Function of erythrocyte cytoskeleton?
Hold the shape of RBCs Peripheral proteins (low ionic strength wash) = spectrin & actin - network attached to membrane by Ankyrin & Glycophorin binding to Band 3 & 4.1
What happens when there is a general deficiency of cytoskeleton?
RBC round up to become more spherical which rupture in capillary beds and cleared by spleen
What is Hereditary Spherocytosis
Depleted Spectrin levels by 40-50% > haemolytic anaemia
RBC lysis > BM production
What is Hereditary Elliptocytosis?
Spectrin molecule unable to form heterotetramers > fragile RBCs > haemolytic aneamia
What types of molecules can pass through membranes?
Hydrophobic
Small, uncharged polar molecules
What type of molecules can’t pass through membranes?
Large, charged polar molecules
Function of Na/K-ATPase?
Electrical excitability
2ndary Active transport for:
pH, cell volume, Ca conc, Na absorption in epithelium, nutrient reabsorption in gut
How are calcium levels controlled?
Na/K-ATPase pump generates Na+ gradient for:
Active Transport - using ATP
PMCA - Expel Ca from cell in antiport with with H+, using ATP
SERCA - antiport with H+
2ndary AT:
NCX - low affinity, high capacity - removing most of Ca
Ca uriporters into mitochondria
What type of operations are PMCA and SERCA?
High affinity & low capacity
NCX in ischemia?
ATP is depleted of X Na pump > Na accumulates in the cell causing depolarisation - reversing the NCX causing Ca entry - high Ca = toxic
Ions responsible for raising pH?
2nd AT - NHE = Na/H exchanger - inhibited by amiloride (K-sparing diuretic)
Sodium-Bicarb Co-transporter (NBC) with Cl/HCO3 exchanger - raising pH
Ions responsible for lowering pH?
Amion exchanger - Cl/HCO3 exchanger - removal of base
What happens if cells swell?
Extrude ions (K, Cl) to lose water
What happens if cells shrink?
Influx of ions (Na, Ca) to gain water
Describe Cystic Fibrosis?
Faulty CFTR > unable to transfer Cl out cells (normally 2ndary AT symport of Cl-) so Cl accumulates in cell > water movies into cell via osmosis > viscous, thick mucous in lumen
What causes diarrhoea?
Over active CFTR by phophorylation by Protein Kinase A - excess Cl- in lumen drawing water
What is resting membrane potential?
The potential inside the cell relative to extracellular
RMP of nerve cells?
-50 to -75 mV
RMP of cardiac/skeletal muscles?
-80 to -90 mV
How is the RMP created?
selective permeability to K+
What is the equilibrium potential?
The membrane potential where there is no net movement of ions across the membrane
What is the Nernst Equation?
Calculation to work out equilibrium potential:
Elon = 61?z log10 [ion]out/[ion]in
What is depolarisation?
membrane potential decreasing in size so that the interior is less negative - causes by opening Na or Ca channels
What is repolarisation?
Increasing membrane potential size so inside is more negative - opening K and Cl channels
difference between fast and slow synaptic transmission?
Fast - receptor = ion channel
Slow - receptor & ion channel = separate requiring G-protein or intracellular messengers to open
The binding of Ach on post-synaptic membrane triggers?
Excitatory post-synaptic potential
Explain sodium’s affect on APs?
depolarised threshold > voltage-gates Na channels open > influx of Na as move to reach their ion equilibrium>influx causes further depolarisation & opens more channels> inactivation > v-gated K channels open > K efflux > depolarisation
Na inactivation = accommodation
What is the Absolute Refractory period?
All Na channels are inactivated, unable to generate an AP
What is the Relative Refractory Period?
recovering Na channels -need large stimulus to generate ab AP
Describe the Na and Ca channels?
similare - 1 peptide of 4 homologous repeat. Each repeat = 6 transmembrane domains with one sensing voltage of the membrane
Describe the K channel?
4 peptides - Each repeat is in fact a subunit with 6 transmembrane domains
List an example of a local anaesthetic?
Procaine - blocks Na channels
Order of block in nerve fibres?
- Small myelinated
- Non-myelinated
- Large myelinated
Sensory before motor
What properties about axons lead to high conduction velocity?
high resistance
high diameter
low capacitance - ability to store charge
What does myelination do?
Increases conduction velocity by reducing capacitance and increasing membrane resistance
Features of propagation?
Saltatory conduction
Nodes of Ranvier
One direction
What is the difference between Schwann cells & oligodendrocytes?
Schwann cells = peripheral axons
Oligodendrocytes = CNS
What is Multiple Sclerosis?
Auto-immune destruction of myelin > decreased conduction velocity / block/ only few APs pass
Describe transmitter release at synapses?
- Ca enters via channels
- Ca binds to synaptotagmin
- vesicle brought closer to membrane
- snare complex makes a fusion pore
- transmitter released via pore
What is a competitive blocker?
Bings at recon. site for Ach
Eg, Tubocurarine
What is a depolarising blocker?
Binds to cause constant depolarisation –> accommodation
Eg, Succinylcholine
What is Myasthenia Gravis?
Autoimmune destruction of nicotinic Ach receptors
Present with drooping eyes, weakness
Tx with Ach-esterase inhibitors (ice on eye lid)
How is Ca gradient maintained?
Impermeability
Ability to expel Ca
Ca buffers
Intracellular Ca stores
What are Ca buffers?
Limit diffusion by binding to Ca, e.g. Calsequestrin and calmodulin
What are the calcium channels found at synapses?
Voltage gated Ca channels triggering Ca influx by depolarisation
Describe the rapidly-releasing Ca stores?
Ca stored in SR & ER by SERCA.
Ligand binds to GPCR> activates G alpha Q > binds to PIP2 releasing IP3 > binding to receptor on SR> triggers Ca release down gradient
Ca induced Ca release (CICR)?
Ca binds to Ryanodine respecters on SR> trigger release of Ca down gradient
Important in cardiac myocyte where initial Ca entry by VOCCs triggered by depolarisation
After release, signal terminated, Ca removed and stores refilled.
Non-rapidly releasable Ca stores?
Ca taken up by mitochondria due to microdomains (regions of high conc) to buffer. Ca uriporters
Mit. Ca used to replenish SR stores via store-operated Ca channels
Describe G-proteins:
& transmembrane domain receptors coupled with a transducing molecule - GTP-binding regulator protein (g-protein) that triggers enzyme or channel activation
Which type of receptors are GPCRs?
Muscarinic - seen with parasymp.
Discuss steroid hormones:
Able to pass through membrane to bind to intracellular receptors which at resting state are bound to heat shock/chaperone proteins which dissociate and translocate to nucleus to alter DNA genre expression.
Slow rate of action as requires changes to transcriptions and translation
What is pinocytosis?
Invaginations of membrane to form lipid vesicles for uptake.
Fluid phase is as it is,
Receptor Mediated Endocytosis = specific binding to receptors for selective uptake
Describe the uptake of cholesterol?
Example of RME:
LDLs in the liver, surrounded by apoproteins. Ldl receptors recognises Apoprotein B > receptors clustered in Catherine Coated Pits > LDL bind > pits invaginated to form coated vesicles.
Vesicles uncut with ATP > fuse with larger smooth vesicles = endosomes > pH of endosomes = lower so LDL and receptor dissociate > endosomes = Compartment for Uncoupling of Receptor & Ligand (CURL)
LDL receptor recycles to membrane.
LDL ruse with lysosomes where cholesterol is hydrolysed into esters > released into cell
Mutations of LDL receptors?
- Non-functioning receptor > X uptake
- Receptor binding normal, but X interaction between clathrin coat & receptor so not concentrated
- Receptor deficiency as X expression
Describe Fe3+ uptake:
Apoptransferrin + 2 Fe = Transferrin > receptor binding > acidic endosome = releases Fe, but receptor & apoptransferrin bound > complex into CURL to recycle to membrane > dissociates
Insulin uptake?
Clathrin pit - insulin binding = conformational change > endosome - insulin still bound > complex goes to lysosomes for degradation = reduces insulin receptors to protect cell
What is transcytosis?
Transfer of IgA from circa to bile in liver.
What is Oral Bioavailability?
Proportion of dose given orally that reaches systemic circulation in unchanged form
What is Therapeutic ratio?
Max. tolerated dose/minimum effective dose
LD50 (lethal dose for 50% people) / ED50 effective dose for 50% people
What is Drug Distribution?
Theoretical volume into which a drug is distributed into
Amount give / plasma conc at time 0
What is an object drug?
Dose is lower than the number of albumin binding sites
What is a precipitant drug?
Dose is greater than number of available binding sites
Class 1 & 2 together makes..?
object drug level is higher due to displacement by class 2 drugs, so can be toxic
Eg, aspirin is precipitant for warfarin
What is 1st order kinetics?
metab. proportional to drug conc. - straight line with log-scale against time, half-life can be determined.
predictable response
What is zero order kinetics?
drug conc higher than Km - enzyme = saturated so rate of decline is constant despite conc.
straight-line when normal conc vs time
What is the loading dose?
When drug admin is steady - reached within 5 half-lives
Describe drug excretion?
free unbound filtered at glom.
actively secreted
urine pH = determinant.
weak acid, like aspirin, attracted by alkaline urine so less reabsorption
vice versa
