Voltage-Gated Ion Channels in
Health and Disease

Voltage-Gated Ion Channels in
Health and Disease

Squid Giant Axon According to Hodgkin & Huxley

Mammalian Neurons Have Several Types of
Voltage-Gated Ion Channels

I. Ca⁺⁺ as a Second Messenger

[Ca⁺⁺]_i Can Act as a Regulator of Various
Biochemical Processes

II. Fine Control of Membrane Excitability

Early Computers Were Made of Thousands of
Identical Electronic Components

ENIAC’s Computational Power Relied on the Specificity of Connections Between Different Identical Elements

Electronic Devices Are Made of a Variety of Specialized Elements With Specialized Functional Properties

Slide 11

Each Class of Voltage-Gated Ion Channel
Has a Unique Distribution Within the Nervous System

e.g., consider a single gene that encodes
voltage-gated K⁺ channels

Alternative Splicing of Pre-mRNA

Variation of Alternative Splicing of pre-mRNA From One Gene Results in Regional Variation in Expression of Four Different Isoforms of a Voltage-Gated K⁺ Channel

HVA Channels Affect Spike Shape
LVA Channels Affect Spike Encoding

Neurons Differ in Their
Responsiveness to Excitatory Input

Some Neurons Respond with a Burst,
Rather than a Train

Thalamocortical Relay Neurons
Burst Spontaneously

Synaptic Input Can Modulate a Neuron’s
Excitability Properties by Modulating
Voltage-Gated Ion Channels

Neurons Vary as Much in Their Excitability Properties as in Their Shapes

Some Nerve Terminals Exhibit
Activity-Dependent Spike Broadening

Dendrites Are NOT Just Passive Cables
Many Have Voltage-Gated Channels That Can Modulate the Spread of Synaptic Potentials

Distribution of Four Types of Dendritic Currents in
Three Different Types of CNS Neurons

Functional Consequences of Regional Variation of Ion Channel Types Within a Neuron

Voltage-Gated Ion Channels in
Health and Disease

Various Neurological Diseases Are Caused by Malfunctioning Voltage-Gated Ion Channels

How Voltage-Gated Ion Channels
Go Bad

Slide 28

Slide 29

Build-up of K⁺ Ions in the T-Tubules Following an Action Potential Can Depolarize the Muscle Cell

Mutations in Voltage-Gated Cl^- Channels in Skeletal Muscle Can Result in Myotonia

Mutations in Voltage-Gated Na⁺ Channels in Skeletal Muscle Can Also Result in Myotonia

Many of These Point Mutations Affect Kinetics or
Voltage-Range of Inactivation

Mutations in Either a or b-Subunits
Can Lead to Similar Symptoms

Slide 35

Slide 36

Different Point Mutations in the Same a-Subunit Lead to Three Different Classes of Symptoms

Voltage-Gated Na⁺ Channels in Skeletal Muscle Can Have Point Mutations That Lead to:

Degree of Na⁺ Inactivation Deficit Determines Whether Paralysis or Hyperexcitability Occurs

Increasing Degree of Persistent Activation Can Switch the Muscle Fiber from Hyperexcitable to Inexcitable

Slide 41

Mutations in Na⁺ Channels in the CNS
Give Rise to Epilepsy - Not to Myotonia

Slide 43

Slide 44

Because Cl^- Channels are Dimers,
Only 25 % of Heterozygotic Channels are Normal