• Lecture 3

• Voltage-gated channels & the Action Potential

• Channelopathies

Learning Objectives

1. Describe the ion substitution experiments performed by Hodgkin and Huxley in elucidating the ion responsible for the biphasic currents obtained in their voltage clamp experiments with the squid giant axon. What pharmacological agents can also distinguish between these currents?

2. Know how to plot and explain the current-voltage relationship of voltage-gated K+ and Na+ currents.

3. Contrast the topology of various voltage-gated channels and discuss their distinguishing structural feature involved in voltage sensitivity.

4. Know how is voltage dependence recognized in single-channel records obtained from voltage steps to different potentials.

5. Predict the result of an ensemble average of many single-channel current records in response to steps to a particular voltage.

6. Plot the probability of Na+ channel opening and the Na+ current obtained as a function of voltage.

7. Describe an action potential in terms of its dependence on the time course of gNa and gK.

8. Discuss the mechanism of Na+ channel inactivation and its control of the refractory period for generation of multiple action potentials.

9. Describe the events taking place in the neuromuscular junction leading to an action potential.

10. Physiologic Principles Underlying Ion Channelopathies11. Examples of ion channel dysfunction leading to disease (The TRP channel

family and CFTR)

The depolarization-induced biphasic current of squid giant axons

Inward sodium and outward currents

Sodium and Potassium whole-cell currents

Topology of a voltage-gated K+ channel

Ion channel topologies

Voltage-gated channels show an increased Po at more depolarized potentials

Non-inactivating K+ channel currents

Inactivating Na+ channel currents

Po of voltage-gated Na+ channels and the resting K+ conductance

Effect of K+ or Na+ channel activation on membrane potential

Mechanism of fast inactivation of voltage-gated channels

The Action Potential (AP) of a Squid Giant Axon

The neuromuscular junction

Signaling in the neuromuscular junction

Atomic Resolution StructuresVoltage-dependent gating

Long SB, Campbell EB, Mackinnon R. Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science. 2005;309:897-903

Channelopathies