lectSides05.ppt
Transcript of lectSides05.ppt
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Voltage-Gated Ion Channels inHealth and Disease
jdk3
Principles of Neural Science, chapter 9
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Voltage-Gated Ion Channels inHealth and Disease
I. Multiple functions of voltage-gated ion channels
III. Neurological diseases involving voltage-gated ion channels
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Squid Giant Axon According to Hodgkin & Huxley
But....
Only Two Types of Voltage-Gated Ion Channels are Required to Generate the Action Potential
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Mammalian Neurons Have Several Types of Voltage-Gated Ion Channels
Why do neurons need so many types of voltage-gated ion channels?
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I. Ca++ as a Second Messenger
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[Ca++]i Can Act as a Regulator of VariousBiochemical Processes
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e.g., modulation of enzyme activity, gene expression, and channel gating; initiation of transmitter release
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II. Fine Control of Membrane Excitability
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Early Computers Were Made of Thousands ofIdentical Electronic Components
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ENIAC’s Computational Power Relied on the Specificity of Connections Between Different Identical Elements
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Electronic Devices Are Made of a Variety of Specialized Elements With Specialized Functional Properties
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Each Class of Neuron Expresses a Subset of the Many Different Types ofVoltage-Gated Ion Channels, Resulting in a Unique Set of
Excitability Properties
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Each Class of Voltage-Gated Ion ChannelHas a Unique Distribution Within the
Nervous System
e.g., consider a single gene that encodesvoltage-gated K+ channels
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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
PNS Fig 6-14
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HVA Channels Affect Spike-ShapeLVA Channels Affect Spike-Encoding
Time
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Neurons Differ in Their Responsiveness to Excitatory Input
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Thalamocortical Relay NeuronsBurst Spontaneously
HCN currentT-type Ca++ current
PNS, Fig 9-11
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Synaptic Input Can Modulate a Neuron’sExcitability Properties by Modulating
Voltage-Gated Ion Channels
RestingFollowing
Synaptic Stimulation
PNS, Fig 13-11C
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Neurons Vary as Much in Their Excitability Properties as in Their Shapes
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Ion Channel Distributions Differ Not Only Between Neurons, but also
Between Different Regions of an Individual Neuron
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Input
Integrative
Conductile
Output
Each Functional Zone of the Neuron Has a Special Complement of Voltage-Gated Ion Channels
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Dendrites Are NOT Just Passive CablesMany Have Voltage-Gated Channels That Can Modulate
the Spread of Synaptic Potentials
PNS, Fig 8-5
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Distribution of Four Types of Dendritic Currents inThree Different Types of CNS Neurons
(S = soma location)
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Voltage-Gated Ion Channels inHealth and Disease
I. Multiple functions of voltage-gated ion channels
III. Neurological diseases involving voltage-gated ion channels
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How Voltage-Gated Ion ChannelsGo Bad
● Mutations● Autoimmune diseases● Defects in transcription● Mislocation within the cell
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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
Na+, K+, Ca++, Cl-
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Phenotypic Variability
Mutations in the Same GeneLead to Different Symptoms
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Different Point Mutations in the Same α-Subunit Lead to Three Different Classes of Symptoms
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Genetic Variability
Mutations in Different GenesLead to Similar Symptoms
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Mutations in Either α or β-SubunitsCan Lead to Similar Symptoms
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Myotonic Muscle is Hyperexcitable
Vm Vm
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Mutations in Voltage-Gated Cl- Channels in Skeletal Muscle Can Result in Myotonia
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Mutations in Voltage-Gated Na+ Channels in Skeletal Muscle Can Also Result in Myotonia
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Mutations Often Affect Gating Functions
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Many of These Point Mutations Affect Kinetics orVoltage-Range of Inactivation
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Increasing Degree of Persistent Inactivation Can Move the Muscle Fiber from Hyperexcitable to Inexcitable
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Voltage-Gated Na+ Channels in Skeletal Muscle Can Have Point Mutations That Lead to:
Potassium Aggravated MyotoniaParamyotonia Congenita Hyperkalemic Periodic Paralysis
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e.g., Voltage-Gated Na+ Channels Found in the CNS And Those Found in Skeletal Muscle
Are Encoded by Different Genes
Regional Differences in Gene ExpressionAccount for Much of the Specificity of
Ion Channel Diseases
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Mutations in Na+ Channels in the CNSGive Rise to Epilepsy - Not to Myotonia
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Understanding Ion Channel Subunit Structure Helps to Explain Aspects of
Heritability of Disease
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•Pharmacological block of 50% of Cl- channels produces no symptoms.
•Heterozygotes with 50% normal Cl- channel gene product are symptomatic (autosomal dominant myotonia congenita).
Paradox
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Because Cl- Channels are Dimers, Only 25 % of Heterozygotic Channels are Normal
Mutant
Wild Type
Genes Channels
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