NEURO 1020: MEMBRANE POTENTIAL MT1

Membrane Hypothesis

RMP

Julius Bernstein, 1902/

1. RESTING MEM POTENTIAL arises from high resting selective permeability to K+ and a concentration gradient for K+ ions across membrane

MAIN IDEA:

CHANGES IN K+ CNTRN SHOULD ALTER VM

Membrane Hypothesis debunking

Hodgkin and Huxley deproved

- giant squid axon

- varied K+ extracellular cntrn and measured Vm-> more depolarized than if just cell was j K+ permeable

Model Cell CRITERIA

1. ELECTRONEUTRAL:

number of - and + charges equal on both sides of mem

2. OSMOTICALLY BALANCED: same number of TOTAL ions on either side (no water movement)

3. No NET ION MOVEMENT-> Cell is at equilibrium

- makes it easy to change membrane potential

Relationship between K+ and Vm

high K+ OUT

low K+ OUT

high K+ OUT:

K+ and Vm has a linear relationship- high resting permeability to K+

- Vm is more positive

LOW K+ OUT:

K+ and Vm has EXPONENTIAL relationship (against membrane hypothesis)

- Na permeability has more weight in determining Vm (MORE DRIVING FORCE)

-Vm more negative

GHK permeability conclusions

if ions permeability is higher, Vm is closer to the equilibrium potential of ion

if two ions are equally permeable, Vm will be in the middle of the Eions

GHK relationship to nernst

GHK is weighted average of nernst potentials

- relative permeability changes weight

E(K) and E(Na)

-75 mV and +55 mV

GHK at 37 degrees Celsius

58 * log (pK[Kout] + .../ pK[Kin] + ... + pCl[Cl OUT]

Vm for Cl-

NEED TO INVERT OUT AND IN CNTRN IN GHK (in / out)

- charge is negative, z = -1

- P(Cl-) has very small effect on Vm because ECl is close to Vm already

- Cl- prevents other ions from taking over GHK, stabilizes

Na-K ATPase

exchanges 3Na OUT to 2K IN

- maintains concentration gradient

-contributes -5 mV to Vm, so INa (current) is 1.5x greater than IK

Membrane electrical circuit modeling

Resistor: ion channel

- K has high conductance, so small resistor

Battery: equilibrium potential determined by Na and K reversal potentials

Hyper or depolarize?

increase K IN

increase K OUT

increase NA IN

increase NA OUT

hyperpolarize

depolarize

hyperpolarize

depolarize

* THINK OF OUT/IN

RMP is determined by

selective membrane permeability to specific ions

- K+, Na+, Cl- are main ions, maintained by pumps

Leigh syndrome

neurodegenerative mitochondrial disorder

- membrane potential channel issues lower ATP/energy production

- hypotonia, deafness, weak immune, hypoglycemia

at rest, cell is most permeable to

K+

low K+ driving force

HIGH NA+ driving force

Vm = -75 mV

Membrane Hypothesis(bernstein)

Action potential

2. ACTION POTENTIAL produced by membrane becoming permeable to all ions (not just K+)

MAIN IDEA:

during an AP, membrane conductance should increase and Vm should = 0 mV

Mem Hypothesis AP debunking

Hodgkin and Huxley

squid axon

- at AP peak, transient reversal of membrane potential inside cell / OVERSHOOT

- due to Na+ -> decreases in extracellular Na+ decreases AP peak

- IF WAS JUST K+, THERE WOULD BE NO OVERSHOOT

overshoot reasoning

- Na+ is necessary for nerves to produce aps

- Na+ reversal potential/ENA is positive -> high Na+ driving force

Ionic basis of AP

1. cell depolarized past threshold

2. Na conductance increase and Na+ influx depolarize

3. overshoot until Vm close to ENa, low driving force

4. Na channels inactivate, K+ conductance increase(VG K )

5. K+ rush out of cell (negative current), cell can hyperpolarize because long lasting increase in g(K) and EK is low

Voltage clamp

"clamp" membrane potential of a cell to measure current

- amplifier compares COMMAND POTENTIAL with measured membrane potential

- current is injected by amplifier until command potential = actual membrane potential/voltage difference

- CANCEL OUT ANY VG CHANNELS by injecting current equal and opposite in sign = no net ion flow

- measure current generated by Vg channels and analy ze

command potential

GOAL potential difference set by experimenter

membrane capacitance

ability of membrane to store charge

- why membrane potential doesn't change immediately with current injection

capacitative current

- a transient current that flows across a cell membrane in response to a voltage change

- can be seen in voltage clamp trace

action potential threshold

point at which net Na and net K currents are equal

- any depolarization after this point = ap

- specific channel composition determines- hillock has higher Na density channels than soma

Na channel blockers

TTX and STX

used to isolate and study individual channel behavior

K channel blockers

TEA

axon hillock ion channel density

highest in the cell

highest probability of ap in axon hillock

further from hillock, less probability of an ap

action potentials are result of

temporally coordinated changes in selective permeability of membrane

squid vs human axons

humans have more diverse channels

- diverse threshold, function, etc

- cells are all plastic- functions can change

channel diversity in humans

- type (ion, speed, threshold, delayed rectifier)

- combination in cell

-geometry of neruon

-alternative splicing

-plasticity

alternative splicing ion channels

- exons included can slightly change how same channel is expressed from cell to celll

- diff splice variants = diff sensitivity

inflammatory hyperalgesia

- depol at soma further down- much stronger

-isopotential (Vm is sam at every part of the cell)-> not true once signals fired

-inflammation increases distance of axon initial segment to soma, causes pain sensitization: inhibitory neuron AP threshold increases

more excitation than inhibition