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35 Cards in this Set
- Front
- Back
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What happens in Myasthenia gravis?
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Anti-nicotinic ACH receptor antibodies associated with thymoma (Cancer)
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What happens in Lambert-Eaton myasthenic syndrome?
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antibodies made against P/Q-type Ca channels with lung carcinoma
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What is saxitoxin?
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Blocker of Na channels
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What are the genetic defects underlying channelopathies?
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Mostly involve point mutations in exons of ion channel subunits
Lead to gain- or loss-of-function of channel |
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How were the were channelopathies of skeletal muscle discovered?
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Intracellular recording from biopsies
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How were channelopathies of the brain and heart discovered?
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Reverse genetics
1. Clinical delineation of familial inheritance 2. Genetic linkage analysis - screen for co-inheritance of detectable polymorphism and disease phenotype 3. Positional cloning |
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What type of inheritance is seen for most channelopathies?
Penetrance? |
Autosomal dominant
High penetrance |
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With what frequency do symptoms occur?
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Episodic attacks with long, symptom-free intervals
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Why do channelopathies normally only affect one organ at a time?
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Because many isoforms occur within ion channel subfamilies (usually on separate genes) and gene expression is highly tissue specific
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What is myotonia?
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Abnormally enhanced electrical excitability of muscle --> bursts of muscle APs --> muscle cannot relax after contraction --> paralysis
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What is periodic paralysis?
What happens to muscle fibers in this state? |
Muscle fibers depolarized and inexcitable during an attack --> recurrent attacks of weakness
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What type of genetic mutation causes myotonia and periodic paralysis
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Missense mutation in ion channels of skeletal muscle
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What ion channel is problematic in myotonia?
How does this affect action potentials? |
Decrease in resting Cl conductance of skeletal muscle
AP threshold lower, lower subthreshold response |
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What is Cl permeability in a skeletal muscle cell?
What is the state of Cl movement at Vrest? |
Cl has high permeability
No net Cl current at Vrest because of this |
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What are the effects of decreased Cl conductance?
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Cl cannot move to stabilize Vrest in response to membrane potential shifts --> repetitive firing
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How does Cl affect Vnernst for K normally?
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AP --> K flows out --> reduces gradient of Kout/Kin --> raises Ek, depolarizes cell
--> Cl in to keep membrane potential stable = Vnernst for Cl = Vrest |
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What are disorders associated with Na channel mutations? (4)
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1. PAM
2. PMC 3. HyperPP 4. HypoPP |
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What is the pathomechanism for Na channel defects?
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Impaired inactivation or enhanced activation --> increased inward Na current --> depolarized muscle
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What are 4 inactivation defects of Na channels?
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1. Incomplete inactivation
2. Slowed inactivation 3. Accelerated recovery from inactivation 4. Depolarized shift in voltage dependence of inactivation (reluctant to inactivate) |
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What are the consequences of a slowed rate of Na channel inactivation? (2)
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1) Longer AP --> increased K efflux --> rise in extracellular K --> depolarization of Vrest --> may trigger AP --> repetitive firing
2) Also, increased Na channels active at end of AP --> higher tendency for next AP firing |
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What are the consequences of persistent Na current?
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small persistent Na in --> depolarization --> inactivates normal Na channels --> muscle fiber unable to fire AP (refractory period) --> flaccid paralysis
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What are the clinical features of benign familial neonatal convulsions?
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Unprovoked generalized or partial seizures
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What are the gene mutations in benign familial neonatal convulsions?
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1. K channel subunit (KCNQ2) expression limited to brain, several mutations --> haploinsufficiency
2. Missense mutation in pore region of K channel subunit (KCNQ3) |
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What current is formed from the pore created by KCNQ2 and KCNQ3?
What is this current's affect on neuronal excitability? |
M-current = K current inhibited by muscarinic agonists (Ach)
Less M current, more excitable |
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What is retigabine?
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Increases the open probability of M-current channels --> inhibited firing
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What is dominant negative suppression?
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Abnormal protein coded by mutant allele inhibits function of normal channel
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What is haploinsufficiency?
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Reduction in total number of functional channels
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How can we test for dominant negative vs. haploinsufficiency?
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Co-express mutant and wild type channels...
If smaller currents than when WT alone --> dominant negative If same currents as WT alone --> haploinsufficiency |
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What is the cellular response to reduced Cl channel activity?
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Repetitive firing due to loss of conductance that stabilizes Vrest
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Sympathomimetics: Catecholamines: List
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-Epinephrine
-Norepinephrine -Isoproterenol -Dopamine -Dobutamine -Phenylepherine -Albuterol -Ritodrine |
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What is the cellular response to gain of function Na channel mutations?
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repetitive APs
plateau depolarization, possible shift in Vrest |
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What does PAM stand for?
What is the defect? What are the consequences? (2 pathways) |
Potassium aggrevated mytonia (no paralysis) - myotonia made worse with K
Na channels inactivate too slowly --> a. Longer AP --> more K efflux --> reduced K gradient --> Ek depolarizes --> more AP b. More Na channels open --> AP |
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What is PMC?
What is the defect? When does it get worse? |
Paramyotonia Congenita
Na inactivates too slow, incompletely Myotonia that gets worse with exercise, may also have paralysis |
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What is HyperPP
What is the defect --> consequences? |
Hyperkalemic periodic paralysis -
Paralysis associated with elevation in serum K, may also have myotonia Incomplete inactivation --> depolarization --> inactivation of normal Na channels --> unable to fire another AP --> paralysis |
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What is HypoPP?
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Hypokalemic Periodic paralysis
Weakness associated with low serum K, no myotonia |
