Voltage-Gated Ion Channels in Voltage-Gated Ion Channels in Health and Disease Health and Disease jdk3 I. Multiple functions of voltage- gated ion channels Principles of Neural Science, chapter 9 II. Neurological diseases involving voltage-gated ion channels Mammalian Neurons Have Several Types of Squid Giant Axon According to Hodgkin & Huxley Voltage-Gated Ion Channels Only Two Types of Voltage-Gated Ion Channels are Required to Generate the Action Potential Why do neurons need so many types of voltage-gated ion channels? But.... [Ca ++ ] i Can Act as a Regulator of Various Biochemical Processes Na + Ca ++ + ++ - - + - - I. Ca ++ as a Second Messenger - - ++ + + + + - - + - - + [Ca ++ ] i + + + ++ - - - - + - - + ++ e.g., modulation of enzyme activity, gene expression, and channel gating; initiation of transmitter release 1
Early Computers Were Made of Thousands of Identical Electronic Components II. Fine Control of Membrane Excitability ENIAC’s Computational Power Relied on the Specificity of Electronic Devices Are Made of a Variety of Specialized Connections Between Different Identical Elements Elements With Specialized Functional Properties Each Class of Neuron Expresses a Subset of the Many Different Types of Voltage-Gated Ion Channels, Each Class of Voltage-Gated Ion Channel Resulting in a Unique Set of Has a Unique Distribution Within the Excitability Properties Nervous System + + + - - - - - - + + + + + + - - - - - - - - - - - - e.g., consider a single gene that encodes voltage-gated K + channels + - - - + + + - - - - + - + - - - - - - - - - - - - - - - - + + + + + + - - - - - - + + + 2
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 PNS Fig 6-14 HVA Channels Affect Spike Shape Neurons Differ in Their LVA Channels Affect Spike Encoding Responsiveness to Excitatory Input Time Some Neurons Respond with a Burst, Thalamocortical Relay Neurons Rather than a Train Burst Spontaneously HCN current T-type Ca ++ current PNS, Fig 9-11 PNS, Fig 9-11 3
Synaptic Input Can Modulate a Neuron’s Neurons Vary as Much in Their Excitability Excitability Properties by Modulating Properties as in Their Shapes Voltage-Gated Ion Channels Following Resting Synaptic Stimulation PNS, Fig 13-11C Dendrites Are NOT Just Passive Cables Some Nerve Terminals Exhibit Many Have Voltage-Gated Channels That Can Modulate Activity-Dependent Spike Broadening the Spread of Synaptic Potentials Last Spike First Spike Spike Broadening (% of max) Firing Rate (Hz) PNS, Fig 8-5 Distribution of Four Types of Dendritic Currents in Functional Consequences of Regional Variation Three Different Types of CNS Neurons of Ion Channel Types Within a Neuron ( S = soma location) 4
Various Neurological Diseases Are Caused by Voltage-Gated Ion Channels in Malfunctioning Voltage-Gated Ion Channels Health and Disease � Acquired neuromyotonia � Hyperkalemic periodic I. Multiple functions of voltage- paralysis � Andersen’s syndrome gated ion channels � Malignant hyperthermia � Becker’s myotonia � Myasthenic syndrome � Episodic ataxia with II. Neurological diseases involving myokymia � Paramyotonia congenita voltage-gated ion channels � Familial hemiplegic � Spinocerebellar ataxia migraine � Thompson’s myotonia � Generalized epilepsy with febrile seizures Na + , K + , Ca ++ , Cl - How Voltage-Gated Ion Channels Go Bad I. Mutations in Different Genes Can Lead to Similar Symptoms � Mutations � Autoimmune diseases � Defects in transcription of normal genes � Mislocation within the cell Build-up of K + � Ions in the T-Tubules Following an Action Potential Can Depolarize the Muscle Myotonic Muscle is Hyperexcitable Cell Action Potential Surface Membrane T-tubule V m V m Cytoplasm Sarcoplasmic Reticulum E K = RT ln K o Ca ++ Release F K i 5
Mutations in Voltage-Gated Cl - Channels in Mutations in Voltage-Gated Na + Channels in Skeletal Muscle Can Result in Myotonia Skeletal Muscle Can Also Result in Myotonia Many of These Point Mutations Affect Kinetics or Mutations in Either α or β -Subunits Voltage-Range of Inactivation Can Lead to Similar Symptoms “Happy families are all alike. Every unhappy family is unhappy in its own way.” II. Different Mutations in the Same Gene Can Lead to Different Symptoms Tolstoy, p.1, Anna Karenina 6
Different Point Mutations in the Same α -Subunit Voltage-Gated Na + Channels in Skeletal Muscle Lead to Three Different Classes of Symptoms Can Have Point Mutations That Lead to: Potassium Aggravated Myotonia, Paramyotonia Congenita, or Hyperkalemic Periodic Paralysis Increasing Degree of Persistent Activation � Can Degree of Na + Inactivation Deficit Determines Switch the Muscle Fiber from Hyperexcitable to Whether Paralysis or Hyperexcitability Occurs Inexcitable Activation of normal Na + channels Hyperexcitability = Na + � channels open, but Myotonia do not inactivate normally + Depolarization Firing + + e.g., endplate potential Persistent inactivation of [K+] o More positive E K normal Na + channels Paralysis Mutations in Na + Channels in the CNS III.Regional Differences in Gene Expression Give Rise to Epilepsy - Not to Myotonia Account for Much of the Specificity of Ion Channel Diseases e.g., Voltage-Gated Na + Channels Found in the CNS And Those Found in Skeletal Muscle Are Encoded by Different Genes 7
Paradox IV. Subunit Structure of Ion Channels Can Influence Inheritance Patterns of •Pharmacological block of 50% of Cl - channels Hereditary Ion Channel Diseases produces no symptoms. •Heterozygotes with 50% normal Cl - channel gene product are symptomatic (autosomal dominant myotonia congenita). Because Cl - Channels are Dimers, Only 25 % of Heterozygotic Channels are Normal Genes Channels Wild Type Mutant 8
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