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Membrane Permeability: ions and polar molecules

cannot cross - impermeable
Na+, Cl-, sugars, a.a.


Membrane permeability: small, uncharged, somewhat polar

molecules can cross
glycerol, ethanol


Membrane permeability: hydrophobic molecules, gases

cross quickly
O2, CO2, N2, cholesterol based steroid hormones, hydrophobic (most drugs)


What is the permeability of morphine?

somewhat, polar therefore can cross the membrane


Heroin permeability across membrane?

crosses fast cuz its acetylated morphine and hydrophobic


Where and why are there ion concentration gradients?

- PM and organelle membranes
- ionic composition differs in cytosol and extracellular environment


Simple diffusion occurs in what direction?

From high to low concentration gradient
- spontaneously therefore delta G is negative when moving from high to low


The energy required to maintain the chemical gradient is delta G (+ve or -ve)

to maintain therefore +ve.
when moving down gradient = -ve


What is the equation for free energy?

delta g = RT ln c
c being c2/c1


If you were to transport hydrophillic solutes across the membrane without aid, how is this down and what is the velocity?

- slowly
- very few solutes have enough activation energy to overcome the barrier
- it must break the solvent-solute (h20) bonds first, pass, then reform


If you were to transport hydrophillic solutes across the membrane with a transporter, how fast would this be?

- with transporter
- reaches same equilibrium but
- FASTer
- lower activation energy needed


Membrane Channels vs Membrane Transporters? Difference in flux, saturation, gated?

very fast
not saturable
gated open/close to stimuli
no gate


Membrane Channels

- solutes flow through rapidly
- via diffusion
- not saturable (rate of transport is dependent on the concentration of the substrate) - down the gradient
- gated: open and close in response to stimuli
- highly selective - many types of channels


Passive Transporters

- facilitated diffusion
- down a concentration gradient
- highly selective - sterospecific (D vs L a.a.)
- transport one molecule at a time; saturable binding sites
- not a continuous pore, changes open/close


How do you increase the velocity of passive transporters?

- increase number of transporters since one transporter transports one set of molecules at a time


Are aquaporins channels or transporters?

Water channels
very fast


How do transporters work?

- substrate binds on one side
- conformational change
- other side opens
- substrate released
- conformational change to original side open


What are GLUT1, GLUT2, GLUT4 transporters and where are they expressed/roles, respectively?

- Glucose transporters
- GLUT1: ubiquitous - RBC and brain; basal glucose uptake (imports glucose)
- GLUT2: liver - removal of excess glucose in the blood; pancreas - regulation of insulin release; intestines; (exports glucose)
- GLUT4: muscle, fat, heart - activity increased by insulin; insulin sensitive and critical for diabetes to increase glucose uptake


Explain the GLUT4- total body glucose uptake graph with time.

- GLUT4 uptakes total body glucose
- insulin regulates GLUT4 uptake
- if normal, GLUT4 transporter will follow the concentration gradient and be selective to glucose
- as you give insulin (without resistance) with time, the glucose uptake increases significantly
- if you take away insulin, there is not a lot of glucose uptake (glut4 decreased) and you are left with lots of glucose in the blood


Active transporter

- transports agains concentration gradient
- pumps
- poweredby ATP hydrolysis
- ion gradients generated across membrane


How are cells kept from swelling?

Water association with Na+. 3 Na+ pumped out due to Na/K ATPase


Ion gradients: Na+, Cl-, K+, Ca2+. Which ones have high concentraton outside of the cell.

Na+, Cl-, Ca2+ - high outside
K+ high inside


What are the 3 classes of membrane transporters:

- Uniporter (one, one direction)
- Symporter (2 same direction, co transport)
- Antiporter (bidirectional, co transport)


Membrane potential is measured in what units? What is the definition?

- a charge imbalance as a result of a charged molecule moved across a membrane
- free energy is different on sides of membrane
- measured in volts


What is the inside of a plasma membrane at rest?

= - 60mV (between -50 to -70)


What is the equation for an electro chemical gradient?

delta G = RTlnc2/c1 + zFdeltaV


Na+K+ ATPase. What are the 4 points that it does?

- generates gradients of Na+ and K+
- controls cell volume (pump out water)
- drives active transport of other species (i.e. secondary active transport of Na+/Glucose)
- electrically excitable (nerve cells)


What is the tertiary structure of the Na+K+ ATPase?

tetramer of a2b2
- a performs the transport


What is the net charge generated by the Na+K+ ATPase?

- +ve net charge OUT
- membrane potential cuz -ve inside


What is the power stroke of this transporter?

- conformational change due to phosphorylation


ATPase transport cycle: Step One

bind 3 Na+ cytoplasmic to inside of cell


ATPase transport cycle: Step Two

Na+ binding stimulates the phosphorylation by ATP on the cytosolic side
- ATP adds a phosphate to the enzyme, ADP released


ATPase transport cycle: Step Three

Phosphorylation causes a conformational change
- release Na+ to extracellular outside
- affinity of Na+ decreased


ATPase transport cycle: Step Four

K+ binds the extracellular side
- this triggers the release of the phosphate group
- dephosphorylation


ATPase transport cycle: Step Five

- dephosphorylation causes conformational change and restore to original shape of the enzyme


ATPase transport cycle: Step Six

- 2 K+ released affinity decreases without P
- and cycle repeats
- this step works agains the concentration gradient but favours the electrical gradient cuz more negative interior and adding more positive


What is a secondary active transporter?

The transport of ion DOWN its GRADIENT can transport another isolute UP its gradient


What is an example of a secondary active transporter?

Na+ glucose symporter.
- Na+ is pumped out of the cell via Na+K+ ATPase
- Na+ is brought back into the cell by going DOWN the gradient
- glucose is brought into the cell in this symporter going UP the gradient
- going UP gradient so its an active transporter


Where is the Na+-glucose symporter located in the body?

- microvilli - intestinal lumen to epithelial cells (between intestine and blood)
- Na+ and glucose are brought into the epithelial cell


What drives the Na+- glucose symporter? How many molecules are needed?

high Na+ gradient outside, needs to go down gradient
- 2 Na+ are needed to drive glucose UP the gradient
(vs 3+ Na+ out for sodiumpotassium pump)


What mechanisms are involved with Na+/K+/Glucose between the epithelial cell and blood?

- NA+ K+ ATPase active transporter
- Na+ is brought out of the epithelial (opposing gradient)
- K+ is brought in
- glucose is brought out via glucose uniporter


GLUT2 is what type of transporter?

- passive transporter
- uniporter
- downhill efflux


How are ion channels gated?

- ligand gated
- voltage gated


How do ion gated channels affect neurons?

- presynaptic (ligand - Ach receptor ion channel)
- post synaptic - action potential response to change in voltage - Na+/K+ (de)polarize


Explain the first step to a nerve impulse?

1. Ach is the ligand that causes a small Na+ influx and slight depolarization
- this occurs in the cell body
- nerve impulse sends the Ach as a signal


In the graph, the second part to change in membrane potential is?

- depolarization
- occurs because of Na+ in = depolarize
- a full Na+ influx


In the graph the 3rd part of the change in membrane potential is?

- K+ efflux (out) = repolarization
- establish potential again


Where does an action potential occur and what does this mean?

- action potential occurs at the top +3-mV
- means the nerve has been fired = reaction
- action potentials are all or none, it must reach the threshold for a fire


What is the ionic composition/gradients in neurons?

high K+ cytosol
low Na+ cytosol


What transmits a nerve impulse?

- action potential
- neurotransmitter


What does the action potential do in a neurotransmitter?

- it carries the electrical signal down the axon


What does the neurotransmitter do in a neuron?

- it carries a signal molecule to the next cell


The Na+K+ ATPase in a neuron causes the _____. Ion voltage gated channels causes the _____.

- electro-chemical gradient
- action potential


What is the structure of the voltage gated K+ channel.

- tetramer
- each subunit with 2 transmembrane helices and a shorter helix - selectivity filter
- 2 outer helices in each subunit interacts with bilyayer
- inner helices contribute to inner pore


What causes the channel to be closed?

The +ve extracellular space interact with the +ve helix dipole from 4 Arg/Lys +ve residues
- electrostatic repulsion pushes down transmembrane helix to pinch off the channel


How is K+ stabilized in the channel/selective?

- K+ interacts with the carbonyl oxygens (O coordinates with unhydrated K+)
- it forms a cage precisely
- stabilizes it and replaces stabilizing interactions with O from water sphere and water molecules


How is K+ channel selective?

- size
- partial negative charges of C=O
- consensus sequence for K+ = gly-tyr-gly-val-thr


How does the K+ pass through?

the gate is opened when the membrane potential changes
- the depolarization causes the outside environment to become more negative and the +ve helices shift up
- open gate and release K+


What is the structure of voltage gated Na+ channels?

- 4 domains
- 6 transmembrane helices (S1-S6) each


Which helices of the voltage gated Na+ channel forms the central channel?

S5 and S6


What helix is the voltage sensor?



What happens to the Na+ channel when the membrane is depolarized?

- voltage change induces conformational S4 (less +ve outside)
- S4 moves up.out of membrane
- channel opens


What helix is the activation/inactivation gate?



How is the Na+ channel blocked?

- S4 voltage sensor helix has 4 Arg/Lys that repel the +ve exterior
- this pushes down on the channel/closed when at resting potential


At what membrane potential is the channel fully open?

-70 mV to +30 mV
- must pass threshold


What causes the S4 to pop up initially in order to open the channel and depolarize?

the neurotransmitter release
- depolarize at cell body to decrease repulsion
S4 pops up


What is the inactivation gate. Fast/slow?

- it occurs quickly
- if u increase the tether u increase the time to close and vice versa


What does the selectivity filter do?

- the part of the pore region that only allows Na+ in


How does the activation gate work?

S5 and S6 helices
form the channel
S6 is the activation gate and allows for the open/close


What are two defective ion channels and their result?

Na+ channels in muscle - causes paralysis
Na+ channels in neurons - stop action potentials i.e. terodotoxin binds Na+ channels of neurons
Na+ channels also inhibited by anaesthetics like lidocaine and cocain to dapen down CNS (anti-epileptic, anti-arrythmic drugs)