20110103 Lecture 2 notes.txt

From Iusmphysiology

  • started here on 01/03/11 at 11AM


Contents

[edit] Learning Objectives

  • Understand the nature of the resting membrane potential
  • Understand the structure & function of ion channels
  • Understand passive/electrotonic conduction
  • Understand the mechanisms underlying action potential generation & propagation
  • Understand how myelination affects action potential propagation

[edit] Ion concentration in mammalian neuronal cells

  • Potassium is high in cells, low in ECF.
  • Sodium is low in the cell and high outside the cell.

[edit] In a liposome

  • Because of trends toward disorder so ions always want to be in equal molar concentration on either side of a membrane.
  • If we let out a positive ion, then we build up negative potential inside the cell.

[edit] The electrical field on the plasma membrane is IV 175 kV/cm

  • The ions will line up along the membrane because the potential causes them to attrack even across the membrane distance.
    • The membrane is only 4 nanometers thick
    • This makes sense because the net charge difference is high.

[edit] The Nernst equilibrium potential (Ex)

  • We have two forces: electrostatic force and chemical force.
  • RTln ([Xi] / [Xo]) gives the chemical energy.
  • The electrical force is given by zxFVm
  • At equilibrium these two forces sum to zero
  • This gives us the Nernst equation: Vm = (RT / ZxF) * ln [Xo] / [xi]
    • Simplifies to Ex = 61.54 / Zx * Log [x0] / [xi]
    • Memorize this because it is sometimes on boards (?).
  • A cell usually has a potential of about -70 mV.

[edit] NA+, K+ ATPas (NA/K Pump)

  • Pumps 3 Na+ out and 2 K+ in.
  • Burns 1 ATP per cycle.
  • Inhibitors like ouabain and digoxin.

[edit] Kir and K2P channels control the resting potential

  • We have ion channels that let ions through.
  • Human ion channels can either let potassium or na through.
  • Two-pore K+ channels have two pores that are linked as the same protein.

[edit] Structure of potassium channels

  • There are multiple subunits in these pores; each has two transmembrane domains.
  • The channel resembles a ?
  • The D loop is important for determine the selectivity of the channel (for an ion like K+).

[edit] Multipolar neuron

  • Neurons have: body, dendrites, nucleus, axon hillock (the initial segment of the axon), axon, and nerve terminals.
  • If we put an electrode in, the potential is -70 mV again.
  • But if we do the experiment in vivo we would find that the resting potential is not stable, is pulses.
    • Why does it oscillate? Perhaps this is how we generate thoughts and nerve impulses.

[edit] Electrotonic spread of depolarization

  • So we fish for squids because they have very long axons that have to act quickly to propel the squid forward.
    • One milimeter thick axons!
  • They poked electrodes into the axons and studied the K+ ions.
  • They injected potassium into the axons.
  • They found that the depolarization could spread along the axon.
    • Sweet, this is probably how neurons work in vivo.
    • We call this passive depolarization.
    • The ions don't travel the lengths of the axons, they just displace their neighbor and this occurs all the way down the axon.
      • spreads in both directions

[edit] Length constant

  • If you inject at a given point, the adjacent areas are depolarized but the depolarization decays over the length.
  • Why does it decay?
    • Because there is some resistance.
    • Because their
    • The decay is proportional to the square root of the diameter times the Resistance(M) over twice the R(a).
      • R(m) is resistance generated by the loss of ions through the membrane which is a function of the circumference because the large the circumference the more loss there will be.
      • R(a) is the resistance inherent in the cytoplasm that fills the axon.

[edit] Stronger depolarizations activated reproducible membrane potential changes resembling those seen in vivo

  • They found that:
    • If enough K+ is injected to depolarize above a threshold, the neruon goes crazy and generates its own depolarization force.

[edit] Self-regenerating squid axon action potential

  • They showed that neurons show a characteristic change upon depolarization.
  • When we exceed the threshold level, (about -55 mV), a polarization peak occurred followed by a repolarization phase.
  • The depolarization is due to the inrush of Na+.
  • Hyper repolarization reaches down to Ek because of efflux of K+.

[edit] Separation of Na+ and K+ currents in squid axon by ionic substitution (voltage-clamp)

  • They used a voltange clamp to change the potential to whatever level they wanted.
  • First they showed that there is some influx of Na, then some outflux of Na.
  • Then they removed Na from the ECF and showed that there was no influx of Na.
  • Then they removed Na from the intracellular space and showed that there was no Na outflux.
  • These were done to confirm their experiments.
  • They showed taht these channels functioned by changes in voltage so they called them voltage-gated channels.
  • Tetrodotoxin inhibits voltage-gated Na channels.
  • Dendrogoxin is a potassium channle inhibitor

[edit] Changes in the permeability to sodium and potassium underlie the shape of the squid axon action potential

  • We don't need to memorize the chord conductance equiation.
    • Know that it is proportional to the conductance of Gm
      • What is Gm

[edit] Membrane topology of voltage-gated cation

  • There is an additional domain (s4 transmembrane domain, with positively charged residudes) that sense the voltage.
  • There are peptide linkers that connect all the transmembrane domains.

[edit] Multipolar neuron

  • Na channels are found predominantly along the axon hillock and the axon.
  • Body = soma
  • Concentration of na channels are lower in body and ?
  • In the axon hillock they thought that the triggering of the sodium channels was probably easier than along the axon.

[edit] Refractory Periods

  • They showed that the action potential can only go one way because of the Absolute refracton period.
  • This occurs because the sodium channels are not functional for a short period after depolarization.
  • During hyperpolarization, one can depolarize again, but it takes a greater change in voltage.

[edit] Multipolar neuron with a myelinated axon

  • Schwann cells wrap around the axon to genreate a myelin insulation.
    • Can generate 200 layers around the axon.
  • This insulation blocks the currents (?).
  • The schwann cells leave 2 micrometer gaps called the nodes of ranvier.
  • The density of the sodium channels at the nodes is very high but there are no delayed reaction K+ channels.
  • The major advantage of myelination is that it speeds up depolarization.
    • This is because without myelination you have to depolarize every channel along the way but with myelination you let the ions bump along in the axon to the next channel where depolarization occurs.
    • Thi sis called saltatory conduction.

[edit] Types of the action potential

  • Boards usually have at least one question about shape of action potential.
  • In the nodes of ranvier, there is no hyperpolarization because there are no DP K channels.
  • The AP decays because Na channels become deactivated.
  • Spaced out.

[edit] Demyelinating disorders

  • MS:
    • Central neruons affected
    • Loss of motor control
  • Guillain-Barre' syndrome
    • peripheral nerves are affected
    • associated with shots / immunizations
  • CMT
    • genetic in etiology
  • Krabbe's disease
    • Genetic in etiology

[edit] Demyelination consequences

  • Decreased propagation velocity
  • Only a fraction of high-frequency spikes propagate
  • Total blockade
  • Ectopic spike generation (decreased threshold or mechanical sensitivity)
  • Cross talk between adjacent demyelinated axons

[edit] Nerve conduction testing

  • We will do a lab about this in TBL with Dr. Kincaid.
  • We can measure via two electrodes.
  • We excite the nerve at the elbow and wrist and look at the spikes (called compound action potential, because it is usually comeing through multiple fibers).
  • By measuring the delay, we can divide the length by time and get the velocity.

[edit] Conduction velocity in peripheral sensory and motor axons

  • Don't need to memorize these
  • Can be up to 120 meters / second (skeletal muscle).
  • Pain is transmitted very slowly, though.
    • So touch is faster than pain.

[edit] Summary

  • Potassium is crucial for resting membrane.
  • Influx of sodium through voltage gated Na channels is important for AP generation.
  • Different cells have different shaped APs.
    • The shape is a function of the expression pattern of Na and K channels in the cell.
  • The velocity depends on the diameter of the myelinated axon.


  • stopped here on 01/03/11 at 12PM
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