6.3 - Nerve conduction Flashcards
what is the asymmetric distribution of ions across a membrane
- In summary:
o Na+ (intracellular < extracellular)
o K+ (intracellular > extracellular)
o Cl- (intracellular < extracellular)
o Proteins (intracellular > extracellular)
what does the asymmetric distribution of ions result in
chemical and electrical driving force
what is a membrane potential
electrical potential difference between the inside of a cell and its surroundings
Why is there an asymmetric distribution
Enables cells to maintain osmotic homeostasis; want to avoid movement of excess water into the cell causing lysis.
describe potassium diffusion across a membrane
K+ conc gradient leads to K+ efflux
K+ efflux leads to charge separation
electrical potential difference starts to drive electrodiffusive flux of K+ back into cell
electrical potential increases until electrical driving force balances chemical driving force
what is the equilibrium potential for K+
-90mv
what is the nerst equation
what determines the resting membrane potential
movement of potassium / sodium ions
Na-K ATPase
why is the conc of K higher on the inside in the first place
can be attributed to the K+ being attracted to the negatively charged proteins and fixed anions inside the cell
what mechanism does the Na⁺/K⁺ ATPase pump work via
electrogenic transport mechanism
pumps 3 Na+ out for every 2K+ in
what does the stoichiometry of the pump result in
a net loss of positive charge which contributes to the polarisation of the membrane
how does the pump work
- binds of three Na⁺ ions to high-affinity sites on the cytosolic face of the pump.
- triggers the phosphorylation of the pump via the hydrolysis of ATP
- leads to a conformational shift to the E2 state, which exposes the Na⁺ ions to the extracellular environment and facilitates their release.
- the pump’s conformational change enhances its affinity for two K⁺ ions, which bind from the extracellular space.
- induces dephosphorylation of the pump, reverting it to its original E1 conformation.
- results in the translocation of K⁺ ions into the cytoplasm.
whats more significant to RMP - pump or channels
channels
pump only contributes to about 2-5 mV
rest is channels
describe the movement of ions to form the RMP - leakage
- Intracellular K+ > extracellular K+, so chemical diffusion of K+ is out
- This means the outside of the membrane becomes more positive and the inside is more negative so K+ diffuses electrically into the cell
- Diffusion occurs until chemical = electrical gradient, and the equilibrium potential for potassium when this happens is -90mV
- Extracellular Na+ > intracellular Na+, so chemical diffusion of Na+ is in
- Makes the membrane potential less negative (Ena = +58mV)
- Extracellular Cl- > intracellular Cl-, so Cl- diffuses in
- Resting membrane potential = -75mV (closer to Ek than Ena, since at rest the membrane is more permeable to K+ than Na+).
Em is the balance of Ek, Ena and Ecl (it is the value for which there is no net charge across the membrane)
why does Ek not equal Em
assumes single-ion permeability.
In reality, cellular membranes are permeable to multiple ions = each exerting its own electrochemical gradient
what is the constant field equation / goldman equation
what does the goldman equation show
- Shows that the greater the membrane permeability to a particular ion, the greater impact that ion will have on the membrane potential
- The overall membrane potential is a compromise between all the equilibrium potentials of the different ions as all the ions act to drive the membrane potential towards their specific equilibrium potential.
- However, the ion to which the membrane is most permeable, has the greatest influence and thus the membrane potential is closest to their equilibrium potential.
what is one assumption of the goldman equation
is that the electrical field is constant across the membrane
simplification works well when considering the bulk of tissue but may not hold true in nanoscopic spaces, such as those found in the brain, where charge density can be spatially heterogeneous.
In these small-scale environments, variations in ion concentrations and local membrane properties can lead to significant fluctuations in the electric field, potentially impacting the resting membrane potential
What characterizes hyperkalemia?
Hyperkalemia is characterized by elevated serum potassium levels exceeding 5.0 mEq/L.
What are some causes of hyperkalemia?
Causes of hyperkalemia include renal failure, cellular shifts due to acidosis, or tissue trauma that releases potassium into the bloodstream.
How does increased extracellular potassium affect the resting membrane potential?
Increased extracellular potassium reduces the concentration gradient across the cell membrane, making the resting membrane potential less negative.
A less negative resting membrane potential decreases the threshold for depolarization, making cells more excitable.
early depolarisation + cardiac arrhythmias
How does patiromer help treat hyperkalemia?
releasing calcium ions and binding to potassium ions in the gastrointestinal tract, swapping calcium for potassium.
Patiromer is not absorbed into the bloodstream due to its large polymeric structure and high molecular weight = no passive diffusion across the intestinal epithelium.
potassium bound to patiromer in the intestines is excreted through feces, reducing the amount of potassium that enters the bloodstream.
What characterizes hypokalemia?
Hypokalemia is defined by serum potassium levels falling below 3.5 mEq/L.
What are some causes of hypokalemia?
excessive gastrointestinal losses, diuretic use, or inadequate dietary intake of potassium.
How does decreased extracellular potassium affect the resting membrane potential?
Decreased extracellular potassium increases the concentration gradient across the membrane, making the resting membrane potential more negative
reduces cellular excitability, making it harder for cells to reach the threshold for action potentials.
what is the RMP of cells
-85 to -60 mV
what happens to the RMP if you change the conc of Na / K / Cl
electrical signalling
achieved by controlling electrical current flow across a membrane
How to derive an ionic current equation for each ion
The ionic current flowing through a membrane can be calculated using ohms law (I= V/R)
and since g(conductance)= 1/R, I=Vg.
By substituting in Em-Eion for V, ionic current can be found using Iion= gion(Em-Eion).
electrical analogue of membrane
fluxes of potassium out of cell and sodium into cell
why is the cell membrane a capacitor
charge separation can be stored here
equation for charge stored on a membrane
demonstrates that the ion fluxes which occur in the generation of an action potential to bring about the change in membrane potential are very small, indicating
that electrical signalling is an efficient process.
what is an action potential
substantive but transient depolarisation of the membrane potential
steps of an action potential
triggering the action potential, depolarisation, repolarisation, hyperpolarisation, resting
state (refractory period)
Graphs of action potential
note how it doesnt reach ENa
phase 1 - Triggering the action potential and depolarisation phase of the action potential
- primarily initiated by excitatory synaptic inputs or sensory stimuli
- leads to the opening of ligand-gated channels.
- channels permit a modest influx of Na⁺ ions, causing a small depolarisation that brings the membrane potential closer to the threshold.
- Once this threshold is reached = triggers a conformational change in the voltage-gated sodium and potassium ion channels.
- results in a dramatic increase in membrane permeability to Na⁺.
- influx of sodium ions creates a positive feedback loop that propels the membrane potential upward toward the sodium equilibrium potential.
repolarisation phase
- VGNaC close
- VGKC open
- Lowers membrane’s permeability to Na relative to K
- Na+ stop entering + get an efflux of potassium ions = decreases RMP back down
hyperpolarisation phase
Membrane repolarisation reduces gK, leading to closure of voltage gated potassium
channels
- Slower decrease in gK so potassium channels remain open for longer
- Leads to an excessive efflux of potassium ions leading to hyperpolarisation/ undershoot
refractory period - 2 phases
Absolute refractory period and then relative refractory period
Absolute refractory period:
period immediately after an action potential in which another action potential
cannot be generated no matter how strong the stimulus
corresponds to the time required for voltage-activated sodium channels to recover
from inactivation
ensures action potential only moves in one direction down the axon
Relative refractory period:
Another action potential can be generated but requires a stronger than usual
stimulus
Increased threshold
Gradually threshold value will return to normal
because only a small number of Na+ are activated - so you need to counteract that with a higher probability of these channels opening
describe the kinetics of the voltage gated Na+ channel
when it passes threshold - S4 segments move outward, triggering a series of rapid conformational changes that result in the opening of the activation gate
the same voltage that opens the activation gate also closes the inactivation gate
HOWEVER - inactivation gate closes slower then activation gate opens - therefore for a brief period of time gate is open
describe the kinetics of the potassium ion channel
DELAYED-RECTIFIER K+ CHANNELS
potassium channels also are triggered by the threshold voltage
BUT
much slower to open - starts to open around the peak of the action potential.
causes an efflux of potassium ions, decreasing the membrane potential and preventing the amplitude from reaching the equilibrium potential of sodium.
why does the action potential not reach the equilibrium potential of sodium
main reason - the very high background permeability of the membrane to potassium is still there during potassium, so by the goldman constant field equation - transmembrane potential coild never reach ENa
it falls back to the RMP because of the sodium and potassium ion channel kinetics
where does the action potential originate in neurones
at the axon hillock (where axon meets cell body)
problem with passive conduction - just allowing the current to diffuse
length + time constant
what is capacitance
determines how much current you have to add or remove from each side of the membrane in order to change the voltage for a given amount
conductance of AP in unmyelinated neurones
Na+ influx in an active patch of membrane creates strong local depolarisation
current flows from active region along the axis of axon via local circuit currents - depolarising adjacent regions of axon
depolarisation causes opening of VGNaC - in these areas - generating another action potential
action potential is regenerated
movement of charge can be mediated by the electrodiffusion of ANY ion
what drives this process of AP conduction in unmyelinated neurones
local circuit currents
one way propagation
orthodromic conduction
AP propogation in myelinated cells
Myelination confined to discrete regions corresponding to individual Schwann cells
Nodes have high densities of voltage-activated channels
Na + influx can generate local circuit currents that can spread very far and fast down the
internodal region (area insulated by the myelin sheath)
On reaching next node, local circuit currents will depolarise that nodal part of membrane
Reaches threshold, voltage gated Na channels in the next node open
Influx of Na +
Generation of further local currents propagate along the axon further
Action potential propagates along nerve by jumping from node to node = SALTATORY CONDUCTION
what are the passive electrical constants of membrane
length constant and time constant
what is length constant
distance for the voltage to drop to 1/e of its original value
typical length constant value
1-3 mm
what is time constant
how much time it takes for the voltage to drop to 1/e of its original value
typical values for a time constant
1-5ms
length constant equation
time constant equation
how does length constant effect conduction velocity
longer length constant - more distant areas of membrane ahead of impulse can be depolarised to threshold
therefore = increases conduction velocity
how does time constant impact conduction velocity
a short / fast time constant means membrane ahead of impulse reaches threshold quicker = increases conduction velocity
what factors influence conduction velocity
fibre diamater
myelination
temperature
magnitude of Na current
how does fibre diameter impact conduction velocity
internal resistance is inversely dependent upon axon cross sectional area.
The membrane resistance is inversely proportional to axon circumference.
Therefore, axons with a larger radius have a larger length constant = increases the conduction velocity.
BUT
axon size does not alter membrane time constant appreciably = decrease in membrane resistance (with increased membrane surface area) is cancelled out by a proportional increase in membrane capacitance.
how does myelination impact conduction velocity
increases membrane resistance
= increases length constant = increases conduction velocity
decreases membrane capacitance = so time constant does not change
VGNaC packed at high density at nodes = large inward current = high conduction velocity
how does myelination decrease capacitance
by reducing the surface area of the axonal membrane exposed to the extracellular environment
Lower capacitance allows the membrane potential to change more rapidly, enabling quicker threshold attainment for action potential generation
prove that myelination does not impact time constant
how does magnitude of sodium current impact conduction velocity
big current = more charge entry + more effective local depolarisation = faster conduction
larger amplitude = larger voltage field = larger length constant = faster
what would happen in neurones lacking VGKC
repolarisation be slower
would be governed by the membrane’s time constant.
primarily dictated by the capacitance of the membrane and the resistance of the cytoplasm.
how does temp impact conduction velocity
High temperature = quicker conduction (Na channels open and close faster at higher temperature
But in vivo; fixed temperature so this isn’t relevant to humans
relationship between diameter and conduction velocity
Fastest conducting fibres are
-A (15-20μm) – myelinated (innervate
skeletal muscle)
-A(2-5μm) – myelinated, sensory (pain
and temperature)
-C(0.5-1μm) – unmyelinated: sensory
Myelinated nerves (over 0.5
micrometre in diameter) conduct AP
faster than unmyelinated nerves
A-delta = acute pain
- Since larger diameter = smaller internal resistance = quicker speed of transmission
C fibres = dull pain
- Transmitted later since smaller diameter and therefore lower conduction velocity
ion channel blockers
TTX
TEA
TTX - tretrodotoxin
Binds to voltage gated Na channels
Physically blocks flow of Na + through the channel, preventing AP generation and
propagation
E.g., poisoning from pufferfish
Eliminates the initial Na + current measured in voltage clamp experiments
TEA - tetraethylammonium
Blocks voltage gated K + channels
increases duration of AP by blocking depolarisation activated delayed rectifier K +
channels
Eliminates the delayed K + current measured in voltage clamp experiments
Also known to reverse the action of drugs like tubocurarine
TEA evokes more release of neurotransmitter and reverses the competitive
antagonistic block of curare drugs
2 distinct types of VGNaC in mammals
TTX sensitive: blocked at nanomolar concentrations, found in neuronal tissues in
body
TTX resistant channel: blocked at higher concentrations, found in cardiac tissue
