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

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

Slide 15

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

Ion Channel Distributions Differ Not Only Between Neurons, but also
Between Different Regions of an Individual Neuron

Slide 20

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

Voltage-Gated Ion Channels in
Health and Disease

How Voltage-Gated Ion Channels
Go Bad

	Mutations
	Autoimmune diseases
	Defects in transcription
	Mislocation within the cell

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

Slide 26

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

Slide 28

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

Slide 30

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

Slide 33

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

Increasing Degree of Persistent Inactivation Can Move the Muscle Fiber from Hyperexcitable to Inexcitable

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

Slide 37

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

Slide 39

Slide 40

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

Slide 42