Biophysics: Channelopathies


Patch Clamping

  • This is a way of recording from neurons without destroying the cell
  • patch pippette forms a high resistance giga-ohm seal with the cell, creating an on cell patch.
  • Negative pressure is then used to **** a bit of the membrane into the pippette, with the inside facing outward, creating an inside out patch. Good for studying 2nd messenger systems.
  • Outside out is made from a whole cell clamp and is the reverse it is good for studying ion channels.

Cell-attached patch recordings

  • A type of patch clamping.
  • Quick inward current characteristic of an Na channel, slow outward current characteristic of a K+ channel.
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Na and K channels

  • Na channels open, and then are inactivated using the inactivation gate, before properly closing.
  • K+ channels only have open and closed states. 
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Gating currents

  • A gating current is the small current that moves across voltage gated channels upon voltage application
  • It is so small that it can only be detected by removing the usual currents that the channel produces using TTX to stop Na channels, or caesium to stop K channels.
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Different types of ion channels

  • The two main types are voltage gated and ligand gated.
  • Voltage gated channels include Na, K, and Ca channels.
  • Ligand gated include the glutamate receptors.

BK channels

  • These are opened by both voltage and intracellular Ca, a combination fo which gives the largest opening. 
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The structure and function of ion channels

Sodium channels

  • Four repeats of six transmembrane domains.
  • The alpha subunit contains the pore  (has the four repeats).
  • TTX binds to sodium channels, but Glutamate->glycine stops this interaction (between s5 and s6 of repeat 1). 
  • A ring of negative charge is how the channel selects for posivie charge 
  • S4 is the voltage sensor and has lots of positively charged residues
  •              It is an alpha helix and membrane potential changes induce conformational changes in               it
  •             When you reduce the positive charge of S4, the gating current is reduced.

Potassium channels

  • 4 proteins of six transmembrane domains, which can be heteromultimeric.
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Inactivation of Sodium channels

  • Follows the hinged lid model.
  • It uses isoleucine, phenylalanine and methionine between repeats 3 and 4
  •                    They form a lid to inactivate the channel
  • If you remove the phenylalanine, the channel cannot be inactivated, and shows behaviour more like potassium channels.
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Paramyotonia congenita

  • It exhibits dominant inheritence and causes muscle stiffness preceded by paralysis
  • S4 of repeat 4 is mutated, which usually couples activation with inactivation

Hyperkalemic periodic paralysis

  • Once again, attacks of muscle weakness triggered by heightend blood potassium levels (4 to 5 mM).
  • Incomplete inactivation of the Na channel

Potassium-aggravated myotonia

  • Aggravated by potassium rich food
  • Mutations in the inactivation loop, whereby a glycine is replaced by a glutamate
  • Causes a slower closure of Na currents. 
  • The presence or absence of paralysis depends on the fraction of Na current that doesn't turn off
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