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. 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 Neurons Expresses a Unique Set of
Voltage-Gated Ion Channels, Which Endows it with a
Specific Excitability Property

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

Activity-Dependent Action Potential Broadening

Length Constant l = √r_m/r_a

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

	Acquired neuromyotonia
	Andersen’s syndrome
	Becker’s myotonia
	Episodic ataxia with myokymia
	Familial hemiplegic migraine
	Generalized epilepsy with febrile seizures
	Hyperkalemic periodic paralysis
	Malignant hyperthermia
	Myasthenic syndrome
	Paramyotonia congenita
	Spinocerebellar ataxia
	Thompson’s myotonia

How Voltage-Gated Ion Channels
Go Bad

	Mutations
	Autoimmune diseases
	Defects in transcription
	Mislocation within the cell

Slide 28

Slide 29

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

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

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

Slide 34

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

Slide 36

Slide 37

Different Mutations in Na⁺ Channels in the CNS
Give Rise to Different Types of Epilepsy

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 42

Slide 43

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