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Lecture 1

Passive conduction in neurones.


What is Active Conduction?

Conduction that requires energy (ATP) and active processes (Na/K) pump to propagate an Action Potential.


What is Passive Conduction? Give an example.

Conduction that requires no enegy - Electrotonic conduction. Synaptic Transmission.


What is Current?

Rate of flow of charge.


Where does current occur in a biological system?

Between the extracellular fluid and axon cytoplasm.


Express current in terms of electrical properties.

Current is proportional to conductance and inversely proportional to resistance of a conductor. I = G x V; I = V / R.


What are the main electrical features of biological systems?

Lipid bi-layer acts as a good resistor and capacitor. Ion channels provide conductance.


What is capacitance?

Amount of charge required to change the membrane potential by x Volts.


What is the role of capacitance in biological systems?

Slow down changes in voltage.


Express conductance in terms of electrical properites.

Proportional to the cell surface / insulator thickness ratio. Q = C x V.


How does capacitance change the trace on a current/time graph?

The trace with no capacitance shows sharp, instantaneous changes in voltage (digital). The trace of a system with a capacitance compotent shows more gradual, parabolic changes in voltage.


What two properties define how gradual the change in voltage is in a neuron?

Time constant. Length constant.


What is the time constant?

Time for the membrane potential to change by 63% of the maximum membrane potential.


How is the time constant expressed in terms of resistance and capacitance?

Tau = Rm x Cm


How is the time constant across a capacitor expressed?

Vc = Vmax(1-e^-t/tau)


How is the time constant across a resistor expressed?

Vr = Vmax(e^-t/tau)


What is the length constant?

Distance from injection site of current at which the response is reduced to 37% of Vmax.


How is the length constant expressed?

Vm = Vmax(e^-x/lambda); x = distance from site of injection of current.


What is the basis of cable theory?

The amplitude of passive responses decreases over distance due to leakage of current.


What are the types of resistance in a neuron?

Axial - resistance of the axon cytoplasm. Membrane - resistance associated with crossing the membrane. External - resistance of the extracellular fluid.


What are the properties of the types of resistance in a neuron?

Ra and Rext are longitudinal and increase with distance. Rm is constant and applies only when current crosses the membrane.


How the amount of current leakage from a neuron be decreased?

Increasing Rm - Myelination of the axon. Decreasing Ra - Increase in axon diameter.


What is the importance of the Rm/Ra ratio?

Rm/Ra1 - Rm is greater than Ra - Current less likely to leak out.


What is electrotonic conduction?

Passive spread of voltage along the axon membrane.


What are the properties of electrotonic conduction?

Can be excitatory/depolarisatory (EPSP) or inhibitory/hyperpolarisatory (IPSP). Proportional to AP conduction velocity. Proportional to Rm. Proportional to diameter of axon.


Lecture 2

Properties of Action Potentials.


What is an Action Potential?

Rapid, transient change in membrane potential.


What are the main properties of an Action potential?

Self-propagating. Invariant within a cell. Varies in different cells. All or nothing response. Frequency limited by refractory periods.


What is refractoriness?

Reduction in membrane excitability following an AP.


How can refractoriness be overcome?

Induction of a larger stimulus.


Describe the types of refractory periods.

Relative - Excitability is reduced but an AP can still occur. Absolute - No excitability, AP impossible.


What are the properties of local current flow?

Proportional to AP velocity. Depends on passive flow of currents along electrical gradients.


How can local current flow be increased?

Increasing length constant. Decreasing time constant.


How does increasing length constant increase local current flow?

Increases length of current circuits.


How does decreasing time constant increase local current flow?

Enhances rate of depolarisation due to more PSPs reaching threshold. Speeds up AP propagation.


What is the evidence for local circuits?

Hodgkin 1937: Small transients recorded after blocking AP conduction by placing neuron on cold metal block. Electrotonic conduction must still occur; Hodgkin&Huxley 1952: Silver wire in a giant squid axon increases conduction (decreased RA). Fairlawn, N.J., Paraffin bath reduced conductance/slowed propagation.


What is saltatory conduction?

Leaping of AP from one node of Ranvier to the next in a myelinated axon.


What is myelination?

Wrapping of axon in a myelin sheath of oligodendrocytes or Schwann cells.


How does myelination differ in periphery and CNS?

CNS - Oligodendrocytes; Periphery - Schwann cells.


Which electrical properties are affected by myelination?

Increased Rm; Decreased Cm; Increased electrotonic conduction.


What is a mesaxon?

Canal connecting the axon to the extracellular fluid through the myelin sheath.


What are the properties of nodes of Ranvier?

Low Rm; High concentration of Sodium channels (centre) and potassium channels (edges).


What are caspr? Where are they found?

Proteins involved in connection of myelin sheath to the axon. Present in nodes of Ranvier between pools of sodium and potassium channels.


What is the evidence for current flow at nodes of Ranvier only?

Huxley%Stampfli 1949: If current is applied at nodes, the magnitude of current needed to reach threshold is smaller. Local application of anaesthetics is more effective at nodes. Current detected at nodes shows AP propagation, internodes show electrotonic conduction.


What is the difference of membrane conductance between myelinated and unmyelinated axons?

Unmyelinated: 1uFcm^-2; Myelinated: 2.5uFcm^-2


What is the difference of membrane resistance between myelinated and unmyelinated axons?

Unmyelinated: 1-3 KOcm; Myelinated: 160 Kocm


What is the difference of AP velocity between myelinated and unmyelinated axons?

Unmyelinated: proportional to sqrt of diameter; Myelinated: proportional to diameter


How does myelination increase the length constant?

Increases Rm - decreases leakage of current.


What are the effects of myelination on the time constant?

Decreases time constant by decreasing capacitance.


What properties of APs are affected by myelination?

Regeneration time. Upstroke. Conduction velocity.


How does myelination increase conduction velocity?

Increases length of local current circuits.


Lecture 3

Ionic basis of Action Potentials


What is an Equillibrium potential?

Membrane potential at which the electrical and concentration gradients are in balance.


How is the Equillibrium potential calculated?

By using the Nernst Equation. E = RT/zF x ln([A]o/[A]i)


What are the properties of resting potential? Explain.

Slightly more positive than E(K). Membrane not entirely selective to K+.


How is the permeability of membrane calculated?

Using the Goldman-Hodgkin-Katz equation.


What causes changes in permeability of membranes?

Action Potentials cause opening and closing of voltage gated channels.


Describe the positive feedback involved in depolarisation.

Depolarisation => Sodium channels open => Sodium influx => Further depolarisation


Describe the negative feedback involved in repolarisation.

Depolarisation => Potassium channels open => Potassium efflux => Repolarisation


What is a voltage clamp used for?

Controlling membrane potential. Measurement of ion movement.


Why is a voltage clamp more useful than radioactive markers?

Greater resolution. Measurements in microseconds rather than seconds or minutes.


How does a feedback amplifier work?

Supplies the cell with an electric current which changes the membrane potential to the desired value. Detects cell's potential and alters it accordingly.


How can the Sodium current be "removed" to show only the potassium current on the trace?

Pharmacological agents. Replacement of Sodium ions. Changing equillibrium potential of sodium to 0mV.


What factors affect current amplitude?

Number of open channels. Conductance of individual channels. Electrochemical gradient.


What is conductance?

Measure of ability to pass ionic currents. Proportional to amplitude of depolarisation.


How could the conductance of K be expressed?

G(K) = I(K)/(Vm - E(K))


Lecture 4

Single Channel Recording


Describe how single channel recording is performed.

Fine glass micropipette is sealed onto cell surface. Microelectrode records ionic currents within the area.


What are the patch clamp configurations used in single channel recordings?

On-cell. Inside-out. Outside-out.


Describe the on-cell patch clamp configuration.

Electrode attached to cell. Small patch isolated.


Describe the inside-out patch clamp configuration.

Patch of cell pulled off. Membrane adheres to pipette. Access to intracellular side of channels possible.


Describe the outsite-out patch clamp configuration.

Cell burst via suction. Tube of membrane pulled off. Access to extracellular side of channels possible.


How are single channel recordings useful?

Allow measurement of probability of opening of channels. Current amplitude and conductance.


What properties of sodium channels have been deduced from single channel recordings?

Stochastic opening. More likely to open soon after voltage change. Inward current. Conductance increases with opening probability. Constant amplitude of voltage change but variable opening time and duration.


Describe the opening system of sodium channels.

Switch between Closed, open and inactivated. Closed by the activation gate (repolarisation). Inactivated by the inactivation gate (absolute RP).


What properties of potassium channels have been deduced from single channel recordings?

Stochastic opening. Opening delayed. Slow, sustained rise in outward current. Open only during depolarisation. Close at negative potentials. Constant amplitude, variable time and duration of opening. Close slowly - sustained opening prevents new depolarisations.


Describe the molecular structure of potassium channels.

Glycoproteins spanning the cell membrane. Form pores. Tetramers of 4 identical subunits.


How many genes are potassium channels coded by?



Describe the structure of potassium VGCs

6 alpha-helical transmembrane domains. T1 and Beta (intracellular regulatory domains).


What are the properties of the TM domains of potassium VGCs?

S1-4 - Voltage sensing domain (S4 contains +ve arg/lys at every 3rd position). S5-6 - Pore-forming domain (P-loop) which forms the selectivity filter.


How are potassium VGCs selective for potassium?

Sleectivity filter slects ions by size and charge. It mimics the hydration of ions via it's carbonyl oxygens.


How are potassium VGCs exploited pharmacologically?

T1 and Beta domains are target sites for most potassium channel inhibitors such as anti-arrhythmic drugs.


Describe the opening system of potassium channels.

Inner helices form an activation gate which spays apart forming an aperture in response to depolarisation. Opening allows for passing of potassium ions and blockers.


Describe N-type inactivation of potassium channels.

A peptide ball binds withing the inner cavity and prevents potassium influx.


Describe the structure of sodium channels.

1 large subunit made up of 4 linked domains that resemble the 6TM helices potassium channels. Deactivation gate between 3rd and 4th domain.


How can the inactivation of sodium channels be inhibited?

Cleaving with pronase. Binding with antibodies.