Membranes Flashcards
What are the general functions of biological membranes?
Selective permeability Communication Recognition of signalling molecules Signal generation in response to stimuli Endocytosis Excytosis
What are the 4 permitted motions of the phospholipid bilayer?
Flexion
Rotation
Lateral diffusion
Flip-flop
What are the effects of cholesterol in the phospholipid bilayer?
Rigid steroid ring restricts motion of fatty acid chain reducing fluidity at high temperatures
Flexible tail reduce phospholipid packing increasing fluidity at low temperatures
What 2 structures are formed when an amphipathic molecule is put into water?
Lipid micelle
Lipid bilayer
What are the functional importance of proteins in membranes?
Facilitate diffusion via pumps and transporters
Create ion gradients via ion channels
Affect the specificity of cell responses
Transduce energy
What 3 modes of motion are proteins permitted to do in the bilayer?
Rotation
Lateral diffusion
Conformational change
NOT FLIP FLOP
How can proteins in the peripheral membrane be removed?
Changes in pH (change their hydrogen bond interactions)
Changes in ionic strength (change their electrostatic interactions)
How can proteins in the integral membrane be removed?
Using detergents
Using organic solvents
(Both compete for non-polar interactions)
Where do proteins destined for the cytosol or mitochondria get translated?
Free polyribosomes
Where do proteins that are to be secreted via exocytosis translated?
Rough ER
Modified and packaged in the Golgi
What are the components of the erythrocyte cytoskeleton?
Band 3 Ankyrin (band 4.9) Spectrin Glycophorin A Band 4.1 Adducin Actin
What is the general structure of cholesterol?
Polar head group
Rigid steroid ring structure
Non-polar hydrocarbon tail
What does mutation in spectrin cause and what are the resulting diseases?
Causes loss of flexibility in red blood cells
Haemolytic anaemias
What are the 2 types of haemolytic anaemias? Describe their pathology.
Hereditary spherocytosis - spectrin is depleted by 40-50% due to loss of 1 spectrin allele
Hereditary elliptocytosis - spectrin cannot assemble properly due to defect in spectrin molecule
What is the pathology of duchenne muscular dystrophy?
Loss of dystrophin leading to loss of membrane stability so that when the muscle contracts, the membrane falls apart
Which molecules are permeable and impermeable to the lipid bilayer?
Permeable - hydrophobic molecules and small, uncharged polar molecules
Impermeable - large uncharged molecules and ions
What are the 3 main fluid compartments in the body, giving an example of each?
Intracellular fluidity - cytoplasm
Extracellular interstitial fluid - cerebrospinal fluid, synovial fluid
Intravascular - blood plasma, lymph
Define hypervolemia
Excess extracellular fluid causing overhydration
Define isotonic and the other 2 extremities
Isotonic - levels of sodium in and out of the cell are equal to osmotic pressure levels
Hypotonic - sodium levels in the cell are low causing inflow of sodium resulting in cell swelling and oedema
Hypertonic - sodium levels in the cell are high causing outflow of sodium resulting in cell shrinkage
Regarding the following ions, which ones are more abundant intracellularly and extracellularly - sodium, chlorine, potassium and calcium
Sodium - more extracellularly
Chlorine - more extracellularly
Potassium - more intracellularly
Calcium - more extracellularly
What are the 3 types of transporters?
Uniport - moves 1 ion/molecule into the cell
Symport - moves 2 ions/molecules in the same direction
Antiport - moves 2 ions/molecules in different directions
What are some differences between active and passive transport in the cell?
Passive - depends on the electrochemical and concentration gradient, energy released exothermically, examples include simple and facilitated diffusion
Active - moves against electrochemical and concentration gradient, uses ATP as fuel, ATPases are good examples
What sets the resting membrane potential of the cell?
The passive flow of potassium out of the cell
Regarding cellular activity, describe the pathology of cholera.
The cholera toxin (CTx) enters the cell through receptor mediated endocytosis - adds an ADP-ribose to alpha subunit of Gs protein - prevents deactivation of the protein - feeds into the increased activity of protein kinase A - an enzyme that increases the activity of the CFTR transport channel leading to more amounts of chlorine leaving the cells causing more water to leave the cell also which results in diarrhoea and dehydration
What is the mechanism of the sodium pump?
An antiport that uses active transport
3 sodium molecules out, 2 potassium molecules in
Drive secondary active transport which controls pH inside cell, regulates cell volume, absorbs sodium in epithelia and takes up nutrients
Why is high intracellular calcium toxic to cells?
High intracellular calcium activated enzymatic pathways which can break down the cell membrane, DNA, ATP and other proteins causing irreversible cell damage
Describe the mechanism of the sodium calcium exchanger (NCX)
A sodium and calcium antiport that acts as a secondary active transport
1 calcium ion out, 3 sodium ions in
Removes most intracellular calcium
On a cellular basis, what can happen when there is lack of oxygen?
ATP can’t be produced because oxidative phosphorylation needs oxygen - lack of ATP results in lack of active transport - sodium pump are unable to function - results in higher of concentration of intracellular sodium - NCX transporter switches directions to compensate for increased intracellular sodium - leads to increase in intracellular calcium which is toxic to cells
Describe the mechanism of the plasma membrane calcium ATPase (PMCA)
A calcium uniport that uses active transport to move calcium out of the cell
Describe the mechanism of SERCA
Sarcoplasmic reticulum calcium ATPase - a calcium and hydrogen antiport that uses active transport, for every calcium that enters the cell, 1 hydrogen molecule is released
How do cells control their cellular pH?
Use of buffers and acid and base extruders
What is the mechanism of an acid extruder and give an example of one
They make the cell less acidic by moving hydrogen out of the cell
Examples: sodium hydrogen exchanger (NHE) and sodium bicarbonate cotransporter
What is the mechanism of a base extruder and give an example of one
Makes the cell more acidic by moving bicarbonate out of the cell
Example: anion exchanger - band 3 aka chlorine bicarbonate exchanger
How much water is in the average human and how is it shared?
~40 - 42 litres
~ 28L is in the intracellular compartment
~ 14L is in the extracellular compartment
What are the types of resuscitation fluids that can be used in a clinical context?
Colloids Crystalloids Physiological fluids Glucose solution Mixture of fluids Blood
What is a resting membrane potential?
The electric potential of the cell that exists as a result of ions moving into and out of the cell membrane
What type of cells have the largest resting potentials and why? What are the value of the potentials?
Cardiac and skeletal muscle cells have the largest membrane resting potentials of ~ 80-90 mV because they have chloride channels which causes chlorine to leak into the cell
What is the resting membrane potential of nerve cells?
~ 50 - 75 mV
What is the definition of an ion channel?
A protein that enables specific ions to cross cell membranes
Influx of which ions cause depolarisation?
Sodium and calcium
Influx of which ions cause hyperpolarisation?
Potassium and chlorine
What are the 3 types of gated channels?
Ligand, voltage and mechanical
What are the 4 types of synaptic transmission?
Nerve cell - nerve cell
Nerve cell - muscle cell
Nerve cell - gland cell
Sensory cell - nerve cell
What are some examples of specialised membranes?
Placenta Kidney tubules Intestinal villi Meninges of the brain Mitochondria
What is neonatal abstinence syndrome?
When a baby suffers from withdrawal symptoms after birth due to exposure to illicit or prescription drugs via placental transfer
What is an action potential?
A change in cell membrane potential that is initiated by a stimulus causing a threshold level to be reached
What influences the magnitude of the action potential?
Concentration of sodium in extracellular fluid
What is the difference between absolute and relative refractory period?
Absolute - period following an action potential when it is impossible to stimulate another action potential
Relative - period immediately following an action potential when it is possible but difficult to stimulate another action potential
What are the 3 states of ion channels?
Open
Closed
Inactivated
What is a graded potential?
Change in membrane potential that varies in size instead of being an all or nothing response
How do local anaesthetics work?
Bind temporarily to voltage-gated sodium channels to prevent generation and conduction of action potentials
What 2 factors affect the propagation of action potentials in nerve cells?
Diameter of the axon
Myelination
Describe the sequence of actions once an action potential has been reached
Action potential reached - sodium voltage gated channels are opened in the axon hillock - depolarisation occurs - sodium spreads further down the axon initiating action potential along the axon - potassium channels open in axon hillock - repolarisation - sodium ions are unable to trigger another action potential in area of axon (absolute refractory period) - occurs further down the cell too (signal propagation)
What is the pathology of multiple sclerosis?
An autoimmune disease that leads to breakdown/damage of myelin sheath surrounding the nerves in the CNS resulting in decreased conduction velocity
What are the 2 types of synapses? Describe them
Chemical
Electrical
What are the differences between the muscarinic and nicotinic receptors?
Muscarinic - metabotropic receptors that use g-proteins
Nicotinic - ligand gated ionotropic receptors that depolarise the cell by allowing positively charged ions to enter
Where can electrical synapses be found?
Cardiac muscle Purkinje fibres Brain stem Retina Bladder Uterus
What is the pathology of myasthenia gravis?
An autoimmune disease caused by antibodies that target nicotinic acetylcholine receptors on post synaptic membranes of skeletal muscle leading to their loss of function, resulting in patients suffering from profound muscle weakness and fatigue
What is a ligand?
Any molecule that binds specifically to a receptor site, resulting in activation of the receptor
What is the structure of nicotinic acetylcholine receptors?
Different subunits each with 4 transmembrane domains
What are clathrin coated pits?
Regions of the cell membrane specialised in receptor-mediated endocytosis
What are G proteins?
A family of proteins that bind with guanine nucleotides to transducer energy produced by agonists binding to and activating receptors
What is the basic structure of a g-protein coupled receptor?
Single polypeptide chain
7-transmembrane spanning regions
Extracellular N terminal
Intracellular C terminal
Give some examples of some g-protein coupled receptors?
Beta-adrenoceptors
Dopamine receptors
Histamine receptors
How do G proteins bind to g-protein coupled receptors and what happens post binding?
Once a ligand/molecule binds to 1 of the 2 binding sites on the GPCRs, the C terminal region inside the cell will couple with the g-protein resulting in a conformational change in the C terminal
Describe the process of a ligand/agonist binding to a GPCR
Ligand/agonist binds to 1 of the 2 binding domains of the GPCR - GDP phosphorylates and becomes GTP - GTP binds to the alpha subunit of the GPCR - alpha subunit separates from the beta and gamma subunit taking the GTP with it - the alpha subunit and beta-gamma subunit can then go ahead to interact with effector proteins independently
Describe the physiology of morphine
A string painkiller that works to reduce calcium influx into pre-synaptic membranes in the CNS and PNS by inhibiting voltage-operated calcium channels (VOCC) which results in reduction of neurotransmitter release therefore reducing pain
In respect to affinity and efficacy, describe agonists and antagonists
Agonists have affinity and intrinsic efficacy
Antagonists have affinity but no efficacy
What is Kd and what do the values mean?
Kd - a measure of a receptor’s affinity
High Kd means low affinity
Low Kd means high affinity
Kd is also the concentration of the ligand required to occupy 50% of the available receptors
What is EC50?
The effective concentration of a receptor that will give 50% of the maximum response
What 3 things are needed for drugs to work at maximum effect?
Affinity to the receptor
Intrinsic efficacy
Specificity to work on the right receptor
What is a partial agonist? What are they used for?
Agonists that have affinity but only partial efficacy at the receptor
Used for pain relief and recreational use
What happens to receptor numbers at low activity and high activity?
At low activity, they increase in number to increase activity
At high activity, they decrease in number to decrease activity
What is a spare receptor?
Receptors can be classified as spare when the maximum response can be achieved without occupying all the receptors
What is the efficacy of a drug?
A measure of how good a drug is at producing a specific response
What 3 mechanisms do antagonists use? Describe them
Reversible competitive antagonism - reversible binding of an antagonist to the orthosteric site of a receptor
Irreversible competitive antagonism - irreversible binding of the antagonist to the orthosteric site of a receptor (irreversible bc the antagonist dissociates slowly or not at all)
Non-competitive antagonism - antagonist binds to the allosteric site of the receptor
What is IC50?
The inhibitory concentration of an antagonist which gives you 50% inhibition of the receptor
What is naloxone?
A high affinity competitive antagonist that can be used to treat drug overdoses like heroin
What is the oral bioavailability of a drug?
Proportion of a drug given orally that reaches circulation unchanged
What are the 2 classes of drugs and what do they mean?
Class 1 - drugs that can be used at a lower dose than the number of albumin binding sites
Class 2 - drugs that have to be used at a greater dose than the number of binding sites
Where do drug metabolism and e creation predominantly occur?
Metabolism - predominantly in the liver, can also be in the kidneys, lungs and blood
Excretion - renal excretion
What is 1st order and zero order kinetics of drugs? Give some examples of drugs that following the types of kinetics
1st order - rate of drug elimination increases as drug concentration increases (most drugs use this type)
Zero order - rate of drug elimination is a constant amount (e.g. heparin, warfarin and aspirin)
How is epinephrine made?
Phenylalanine hydroxylated to tyrosine - tyrosine is hydroxylated to DOPA - DOPA is decarboxylated to dopamine - dopamine is made into norepinephrine - norepinephrine transferased to epinephrine
By what 2 mechanisms can noradrenaline be removed?
Termination - re-uptake into the presynaptic terminal by a sodium dependent, high affinity transporter
Metabolism - in presynaptic terminal, noradrenaline that has not been taken up into vesicles can be metabolised by 2 enzymes: monoamine oxidase and COMT
Give an example of a drug that acts on adrenergic nerve terminal
Alpha-methyl-tyrosine
Alpha-methyl-DOPA
CarbiDOPA
What are opioids and what are they used for?
Proteins that act on opioid receptors in the brain and spinal cord leading to increased potassium leaving the cell causing hyperpolarization resulting in reduced pain
What can repeated exposure to drugs cause?
Desensitisation Tachyphylaxis Resistance Dependence Tolerance
What is the BNF?
British National Formulary - contains a comprehensive list of all drugs licensed in the U.K.
