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19 Cards in this Set
- Front
- Back
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__________ is the term for skeletal muscle stiffness due to excessive excitability. ______ is the term for “clumsiness of gait.” ________ is defined as spontaneous, involuntary quivering/twitching muscle contractions.
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Myotonia
Ataxia Myokymia |
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_________ is the general term for diseases of ion channels.
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Channelopathies
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As opposed to Hodgkin and Huxley’s studies on the _______ axon, which contains only ____(#) types of voltage-gated channels, there are _______(~#) types of voltage-gated ion channels in vertebrate neurons.
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Squid
2 hundreds (of) |
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There are many different types of neurons in the body, and most neurons themselves contain several types of channels. These channels are distributed to the four functional regions of the neuron (NAME THE REGIONS) at varying levels. The variety in types and distribution of channels within an individual neuron is responsible for the different _________ of neurons.
Channels also have a unique distribution within the whole nervous system (this is known as “________”). This is evolutionarily advantageous, because it results in _________ of ion channel diseases. (In other words, a genetic mutation of a common channel will only affect a discrete region of the body.) |
4 regions: input, integrative, conductive, output
excitability properties segregation of channels regional specificity |
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Gene mutations that affect ion channel function usually affect what property?
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Gating (i.e. voltage range and kinetics)
(Note: it does NOT generally affect selectivity or conductivity) |
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Describe Phenotypic Variability and give two examples.
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Different mutations of the SAME gene can lead to DIFFERENT phenotypes.
**Ex 1: depending on where the mutation occurs in the gene encoding for skeletal muscle voltage-gated Na+ channels, you could get 1.) K+-aggravated myotonia, 2.) myotonia that is insensitive to K+, or 3.) a more severe form of hyperexcitability (myotonia) that eventually leads to hyperkalemic periodic paralysis. This is a result of failure of inactivation in the mutated channels, which leads to extreme depolarization and therefore permanent refractory even among the non-mutated channels. **Ex 2: different point mutations in the same K+ channel gene can lead to a different cluster of symptoms: 1.) ataxia with myokymia, 2.) epilepsy with myokymia, or 3.) isolated myokymia (or really any combination of these symptoms). |
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Describe Genotypic Variability and give two examples
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Different mutations in DIFFERENT genes can lead to SIMILAR phenotypes.
**Ex 1: mutations to Na+ channel genes or Cl- channel genes in skeletal muscle can both lead to myotonia, since the failure to deactivate Na+ channels (hyperpolarization) or failure to activate Cl- channels (lack of repolarization) will both have the same overall effect (i.e. hyperexcitability). **Ex 2: mutations in alpha OR beta subunits of a voltage-gated Na+ channel in cortical cells can lead to similar effects: generalized epilepsy with febrile seizures. |
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Give an example of regional differences in gene expression and the result of these differences in terms of voltage-channel pathology.
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Ion channel diseases tend to show “regional specificity” due to regional differences in gene expression.
For example: The voltage-gated Na+ channels in the skeletal muscle and in the CNS are encoded by different genes. Defects in the CNS genes will lead to epilepsy, while defects in the skeletal muscle genes will lead to myotonia. |
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Ion channels encoded by the exact same gene can display very different excitability properties. How does this happen? Give an example of this.
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Genetic information for encoding channels can be expanded via:
1.) Alternate splicing of the pre-mRNA 2.) Post-transcriptional editing of the mRNA For example: There are 4 different isoforms of K+ voltage-gated channels that localize to different regions of the brain. These channels arise from the same gene; their differences result from alternative splicing of the same pre-mRNA transcript, which can happen because the different neurons contain different splicing enzymes. |
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What common property in the structure of voltage-gated channels accounts for much of the channel diversity in the body?
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Voltage-gated channels are made up of SUBUNITS (generally alpha, beta, gamma → with alpha serving as the channel pore). These subunits are all encoded by DIFFERENT GENES. This allows for a huge number of combinatorial possibilities in creating of ion channels with very specific excitability, conductivity, selectivity properties, etc.
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Give four examples of how voltage-gated channels can “go bad” and lead to neurological diseases.
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1.) Gene mutations (Phenotypic variation vs. Genotypic variation)
2.) Autoimmune processes 3.) Transcritpional defects -- Normal channels expressed in wrong locations (or too much or too little expression) 4.) Toxins |
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Explain the computer analogy of the nervous system.
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Back in the day, computers were powered via specific connections of identical elements. For a decade or two after the Hodgkin and Huxley experiments, this was how we viewed the nervous system. But now we know that though the networking of neurons is an important aspect, the specialized properties of individual classes of neurons -- i.e. response to synaptic input, spontaneous activity, modulation ability, neural regional variation -- is also critical. This latter framework is more akin to modern electronic devices, which are made up many different, specialized parts communicating together.
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The input zone is located in the _______ region and contains _______ channels. The integrative zone is located in the _______. It contains a high density of ______-threshold _____ channels. The output zone is located in the _________. It contains a high density of _____ channels, which are important for ________ release.
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Dendritic
Pretty much all types and distributions of Proximal axon (Axon hillock) low Na+ Axon terminus Ca++ Neurotransmitter |
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Give some examples of what may be affected in point mutations of genes encoding for voltage-gated ion channels.
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Activation
Inactivation (leads to myotonia) Voltage range/sensing Ion pore structure |
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In addition to K+/Na+/Cl-, Ca++ also has its own voltage-gated channels. Why is Ca++ important for neural signaling?
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Remember: The end goal of the action potential is to modulate Ca++ levels.
**Ca++ serves as a 2nd messanger that: 1.) Modulates enzyme activity 2.) Modulates channel gating 3.) Modulates gene expression (via calmodulin) 4.) Initiates transmitter release ** PLUS -- it can also carry a depolarizing current |
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_________ relay neurons convey info from the thalamus to the cortex and have _________ bursting properties which come about because of the _____ current. The early phase of the pacemaker potential is driven by the opening of these non-specific cation channels when the cells are _________. In a later phase, the ______ channels open, which contributes to further cell ___________.
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Thalamocortical
Spontaneous HCN Hyperpolarized T-type Depolarization |
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Multiple sclerosis is an example of how ________ of functionally normal channels (in this case _____ channels) can lead to dysfunction. MS is believed to be an ____________ disease that affects the _______ on the neuron. This leads to ________ conduction velocity.
What is the compensatory response to the primary defect in MS and how does this affect the neural cell? |
Overexpression (or – abnormal expression)
Na+ (specifically, Na+ 1.6 channels) Autoimmune Myelin sheath and oligodendrocytes slowed With the decrease in myelination, Na+ channels -- which are normally localized to the Nodes of Ranvier -- overexpress and spread out across the entire axon. The excess Na+ channels are unable to inactivate completely, so there is a persistent Na+ influx. This increase in intracellular Na+ affects the Na+/Ca++ exchangers. Normally, the role of Na+/Ca++ exchangers is to keep Ca++ out of cell, but with the increased cytoplasmic Na+, the exchanger reverses and actually brings Ca++ into the cell. High Ca++ levels in the cell activates certain proteolytic enzymes and eventually results in cell destruction. |
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Explain how ion channel subunit structure can explain the inheritability patterns of certain diseases.
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The example given is the dimeric Cl- channel. Remember that Cl- channels are critical for repolarization in SKELETAL muscle (not in the CNS), and a mutation in these channels will lead to hyperpolarization and resultant MYOTONIA. Normally, a block of 50% of Cl- channels (say, a pharmacologically-induced block) would have no physiological effect. But someone who is heterozygous for a mutated gene for Cl- channels (in other words, has 50% abnormal Cl- channel genes) WILL show an effect. Because of the dimeric nature of the channel, the heterozygote with 50% mutated genes only has a 25% chance of creating a channel with two wild-type subunits. The other 75% will have at least one mutated subunit. Since the Cl- channel is a dimer, and since the two subunits modulate each other’s activity, a person with 50% “healthy” genes will only be able to produce 25% “healthy” channels. This is a DOMINANT-NEGATIVE EFFECT.
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Neurons have different input-output ratios. In other words, neurons differ in their ______ to excitatory input. Some neurons have a constant, steady _______ train. Some have an initial train and then begin to show _____, also known as _______, due to slow-opening K+ channels. Some have delayed response due to an initial rapid outward ____ current, which resists ___________. The channels for the delayed response are ____-threshold and eventually _______. A neuron’s excitability can also be modulated. For example, synaptic stimulation using _______ makes _____ channels more excitable and less susceptible to _________.
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Responsiveness
Spike Fatigue Adaptation/Accommodation K+ depolarization Low Inactivates Acetylcholine K+ fatigue |
