general structure = glycerol backbone, 2x FA(C16/18), phyosphate group and head group (cholines,amines, amino acids, sugars...)
exception = spingomyelin - non glycerol backbone
describe the structure of cholesterol
polar head group
4 rigid planar steroid rings
non polar hydrocarbon tail
what is a glycolipid?
replace phospho-headgroup with a sugar
cerebrosides - monomer
gangliosides - digosaccharides
what are the properties of amphipathic molecules?
contains both hydrophillic and hydrophobic moieties
describe the process of formation of lipid bilayers
VDW attraction of hydrophobic tails stabilised by non-covalent, electrostatic and hydrogen bonds
hydrophillic moieties interact with water
what is the difference between peripheral and integral proteins?
peripheral held by electrostatic and hydrogen bonds - washed off by pHand ionic solutions
integral within the membrane held by non polar interactions washed off by detergents/organic solutions
what is the point of membrane assymetry?
allows proteins to carry out their function
the internal and external surface are different maintaining different external and internal environments
describe the fluid membrane model
membranes are fluid structures:
lipid molecules can move in four ways flexion, fast axial rotation, fast lateral diffusion, flipflop.
what is membrane fluidity?
unsaturated bonds (double cis bonds) disrupt packaging of phospholipids increasing fluidity of the membrane
what is cholesterols role in the membrane?
increase stability and increase fluidity
abolishes the endothermic phase transition of phospholipid bilayers - bonds by Hydrogen bonds to the beta-OH group on the FA so the polar ring structure reduces the mobility of the upper part of the FA tail stabilising the structure but also decreasing packing and thus increasing fluidity
how can proteins move?
what stops proteins moving?
restricted by: tethering, aggregation, interaction with other cells, the lipid mediated affect (preference for lower cholesterol)
describe the cytoskeleton and its purpose
restricts lateral movement of membrane proteins and in RBCs allows for the necessary deformation to fit through small capillaries
network of spectrin and actin
what are haemolytic anaemias?
problems with erythrocyte skeleton > reduced RBC lifespan and bone marrow incapable of compensating
hereditary spherocytosis - spectrin levels depleted by 40-50%
hereditary eliptocytosis - spectrin can't for m hetromeres
how do cells resist swelling?
how do cells resist shrinkage?
what are the properties of solutes that affect their movement through membranes?
hydrophobic - will go - eg: O2, CO2, N2, benzene
small uncharged polar molecules - will go - eg: urea, water, glycerol
large uncharged polar molecules - wont go - eg: glucose, sucrose
ions - wont go
what are the differences between passive diffusion, facilitated diffusion and active transport?
passive: permeability and conc gradient
facilitated: uses ion channels/ gated pores
active: against conc/electrical gradient, uses energy
how are ion concentrations regulated?
Na/K ATPase - K in Na out
Ca ATPase - (SERCA) - Ca into SR H out
Na/Ca exchanger - (NCX) - Na in Ca out
what are the ion concentrations intra and extracellularly?
OUTSIDE: K=4mM, Na=145mM, Cl=123mM, Ca=1.5mM
INSIDE: K=155mM, Na=12mM, Cl=4.2mM, Ca=0.0001mM
what is secondary active transport?
symports and antiports using the Na gradient to move sugars, amino acids, ions
symports - same direction - Na/glucose transporter
antiports - opposite directions - NCX
how is the pH of cytoplasm regulated?
sodium/pottasium ATPase creates a gradient for the NHE (sodium hydrogen exchanger - antiport Na in H out) - acidification opposed
how do changes in ion channel activity cause changes in membrane potential?
channels are opened in two main ways: ligand gating and voltage gating
opening/closing changes permeability and thus membrane potential
what are the roles of membrane potential in signalling?
action potentials in nerves and muscles trigger and control muscle contractions and control secretion of hormones and neurotransmitters
what is a synaptic potential?
eg between nerve and muscle, nerve and nerve, nerve and gland
what is the difference between fast and slow synaptic transmission?
fast - the receptor is also a ligand gated ion channel, depolarising transmitters such as ACh and glutamate open channel to let in sodium, calcium and cations causing excitation of the cells the change they cause is called EPSP (excitatory postsynaptic potential).
slow - the receptor is not itself an ion channel but signals to the ion channel via a G protein either within the membrane or through intracellular messengers
what do hyperpolarising transmitters do?
eg. GABA and glycine
open channels to let in/out K or Cl they lead to inhibition the change they cause in the membrane potential is called IPSP - inhibitory postsynaptic potential
what are the properties of action potential and its ionic basis?
action potential = a change in voltage across the membrane
only occurs if threshold is reached - all or nothing
they are propagated without loss of amplitude
Na channels open then Na channels close and K channels open
what is refractiveness?
after an action potential most of the sodium channels have been inactivated by maintained depolarisation the absolute refractive period is where nearly all the sodium channels are inactivated and during the RRP the sodium channels are recovering during this period it is more difficult to fire an action potential
this is the reason action potential only travels in one direction
what is accommodation?
the longer a stimulus last the larger the depolarisation necessary to initiate an action potential > the threshold becomes more positive > Na channel excitability is limited - hence why we use Ca in the heart
what are the molecular properties of ion channels?
large membrane spanning proteins with an aqueous pore
which can be opened or closed by conformational change
sodium and calcium have 1 subunit
potassium has 4 subunits
how do local anaesthetics work?
block the sodium channels
they are weak bases and cross the membrane in an unionised form
they work best when the channel is open and have a higher affinity for inactivated channels
drugs could also stop action potential by blocking neurotransmitter release or binding to the anions involved
how is conduction velocity measured?
distance between anode and cathode / time
how are axons raised to threshold?
action potential is initiated by depolarisation to -55mV -threshold
describe the local circuit theory of propagation
depolarisation of a small region of a neurones plasma membrane produces transmembrane currents in neighbouring regions depolarising them
as the sodium channels are voltage gated this causes more of them to open propagating the action potential
what is the relationship between conduction velocity and fibre diameter?
in myelinated neurones conductance velocity is proportional to diameter - max velocity =120m/s
in unmyelinated neurones conductance velocity is proportional to the square root of diameter - max velocity = 20m/s
what is myelination?
cells begin to be myelinated about 4 months after fertillisation
myelin reduces capacitance and increases the resistance of the axon
peripheral axons are myelinated by schwann cells
in the CNS oligodendricytes myelinate axons
in myelinated axons saltatory conduction occurs
myelination allows for increased conduction without incresed diameter
what is saltatory conduction?
sodium channels are grouped at the unmyelinated nodes of ranvier
because the cytoplasm is electrically conductive and the myelin prevents the leak of charge depolarisation at one node of ranvier is sufficient to raise the next node to threshold and trigger an action potential
this reduces energy expenditure and increases speed
internodal distance is about 1mm
what is demyelination?
caused by diseases
CNS- multiple sclerosis (all), devic's disease (optic and spinal cord)
complete demyelination - slow motor skills as nerve gradually becomes an unmyelinated nerve
could potentially treat with a k channel blocker as they lengthen action potential increasing the chances of propagation
how do action potentials open calcium channels in the cell membrane?
at the nerve terminal depolarisation opens voltage gated calcium channels
calcium enters the cell raising its intracellular calcium concentration and this causes the cell release neurotransmitter by exocytosis
name some types of calcium channels where they are found and what blocks them
L - neurones, muscles, lungs - DHP EG. nifedipine used to treat some heart complaints
N - neurones - w-CTx-GVIA, produced by asian snail > death
P/Q - neurones - w-aga-IVA
R/T - neurones, heart? - Ni2+
outline fast synaptic transmission
1. calcium ions enter through calcium channels
2. calcium ions bind to synaptotagmin
3. vesicle brought close to membrane
4. snare complex makes fusion pore
5. transmitter released through pore
at the motor nerve terminal this transmitter is ACh it then binds to the nACh on the post synaptic membrane changing the conformation of the protein
describe myasthenia gravis and describe a type of drugs which work in a similar way
myasthenia gravis is a disease targetting nACh receptors, patients suffer with profound weakness which worsens with exercise, it is an autoimmune disease
drugs can also block this receptor by binding at the recognition site of ACh there are two types competitive blockers (tubocurorine) and depolarizing blockers (succinylcholine)
why is it important to be able to control calcium ion concentration in our cells?
too much calcium for too long is toxic to cells but many cellular events (enzyme activity, mobility, cell cycle progression, secretion...) rely on raised calcium we therefore need to be able to make it go up and back to normal.
what mechanisms can we use to maintain calcium at its basal level?
when intracellular calcium rises it binds to calmodulin a signal transducer this then binds to PMCA a Ca-ATPase which removes calcium
NCX works best a resting potential and is an antiporter moving 3 sodium ions in for every 1 calcium ion it moves out
what mechanisms can we use to raise intracellular calcium?
depolarisation of the membrane opens VOCCs increasing the intracellular concentration
ligands such as glutamate bind to receptor operated calcium channels such as NMDA and AMPA
it can also be released for intracellular store in the S/ER by two mechanisms: 1. GPCR - IP3 acts on IP3 receptor on the S/ER. 2. CICR - calcium induced calcium release - calcium ions act on ryanodine receptors on the S/ER
what mechanisms do we use to get rid of extra calcium so we can return to basal levels?
there are 3 parts to this - termination of signal, calcium ion removal and calcium ion store refilling
stores are refilled by recycling the released calcium SERCA (calcium/hydrogen antiporter) uses ATP to move calcium back into the S/ER. if this is not properly refilled the S/ER releases a depleted signal and the membrane protein SOC lets some calcium into the cell.
mitochondria also play a part as a non rapidly releasable store
how do cells communicate with each other?
hormones - endocrine signalling - between cells in different tissues via the circulation
neurotransmitters - synaptic signalling - specialised junctions in the nervous system
local chemical mediators - paracrine signalling - between adjacent cells in the same tissue
most signalling molecules are hydrophillic but thyroid and steroid hormones are hydrophobic and travel on carrier proteins and bind to intracellular receptors
what is a ligand?
a small molecule that binds specifically to a receptor site
can be an agonist, antagonist or partial agonist
what is a receptor?
a molecule that recognises a specific ligand or family of ligand and in response to ligand binding brings about regulation of a cellular process
how are ACh receptors classified?
ACh receptors are affected by the binding of ACh
they are then divided based on other things that antagonise them into: nicotinic and muscarinic receptors
muscarinic receptors are then divided into M1, M2 and M3 which are coded for by different genes and each have a 'strongest' agonist
what are the similarities and differences between receptors and enzymes?
similarities = specific, governed by shape, normally reversible
differences = affinity of ligand binding is stronger than substrate, ligand is not modified but substrate is.
what are the roles of receptors?
signalling in response to hormones and chemical mediators
control of gene expression
release of intracellular calcium stores
what is the point of signal transduction?
what are the four ways in which it happens?
most signalling molecules can't cross the plasma membrane and so must interact with a receptor at the cell surface, this binding is then transduced into an intracellular signal in one of 4 ways:
1. ligand gated ion channels - fastest - agonist binding > conformational change > flow of ions down electrochemical gradient > electrical event at plasma membrane eg. nAChr, GABAr
3. seven transmembrane domain receptors/G protein coupled receptors - coupled to effector molecule by a transducing molecule, a G protein. eg. mAChr, adrenoceptors, opiod/light/5-HT/purine receptors
4. intracellular receptors - steroid hormones (cortisol/testosterone/oestrogen) and thyroid hormones (T3/4) pass through the plasma membrane and bind to receptors in the cytoplasm or nucleus > receptor dissociates from chaperone > binds to DNA sequence > regulates DNA expression
extracellular signalling molecules are in very low concentration why does this not matter?
the pathways allow for amplification
what happens when NA binds B1 adrenoceptors on the cardiac pacemaker cells?
what happens when ACh binds M2 receptors on cardiac pacemaker cells?
what happens when insulin acts on hepatocytes?
what happens when glucagon acts on hepatocytes?
what is pinocytosis?
the invagination of the plasma membrane to form a lipid vesicle
it allows for the uptake of impermeable extracellular solutes and the retrival of the plasma membrane it is divided into two forms fluid phase and receptor mediated endocytosis
what are the basics of receptor mediated endocytosis?
specific uptake of substances into the cell due to binding of specific receptors