Term
| Hodgkin-Huxley Approach to Defining Parts of AP |
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Definition
- saw that AP peaks decreased w/ decreasing extracellular Na+ concentration
- hypothesized that Na+ might be responsible for current of AP
- used choline instead of sodium (membrane not permeable to choline) to determine whether Na+ causes early current
- early current eliminated
- subtract Na+-free current from total current to isolate early current
- predicted K+ responsible for late current due to empirical observations (could not be definitively determined otherwise)
- toxins used
- TTX (tetrodotoxin) - blocks voltage-activated Na+ channels (early current)
- TEA (tetraethylammonium) - blocks voltage-activated K+ channels (late current)
- to determine ionic basis of action potential:
- measure ionic currents over wide range of membrane potentials
- isolate sodium and potassium currents
- pharmacological methods: TEA/TTX
- use modified Ohm's to convert to conductance values
- derive equations to describe gna and gk as function of Vm AND of time
- reproduce AP w/ iterative algorithm
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Term
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Definition
- toxin used as pharmacological method of current isolation
- tetraethylammonium
- blocks voltage-activated K+ channels
- blocks late current; isolates early current
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Term
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Definition
- toxin used as pharmacological method of current isolation
- tetrodotoxin
- blocks voltage-gated Na+ channels
- blocks early current; isolates late current
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Term
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Definition
- Inaccurately applied to voltage-gated sodium channels
- sodium channels use inactivation gate
- A-type potassium channels are where idea for model comes from
- Mechanism of channel inactivation first discovered in A-type potassium channels (fast inactivating K+ current)
- The ‘ball’ is a clump of amino acids that binds to a site in the inner vestibule of the channel upon depolarization
- Mutation &/or deletion of the ~80 amino acids between the amino terminus and S1 alpha helix eliminated inactivation
- Inactivation restored by adding a synthetic peptide matching the 1st 20 amino acids in the N-terminal chain to the intracellular solution.
- Similar experiments identified the intracellular loop between domains III and IV of NaV as the inactivation ‘gate’
- (also called the domain III-IV linker)
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Term
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Definition
- Intracellular pronase (general peptidase) removes inactivation, but does not alter activation, suggesting they are mediated by different parts of the channel and are separate processes.
- peptidase removes intracellular/cytoplasmic portion
- shows that inactivation on cytoplasmic side independent of activation[image]
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Term
| Capacitive and Gating Currents |
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Definition
- capacitive current is the nearly instantaneous distribution of charge across membrane in response to stimulus
- the opening of channels requires movement of charge across membrane, so this should add to capacitive current
- gating current found by solving for the difference between the initial current when hyperpolarizing and depolarizing neuron by same magnitude
- hyperpolarizing - capacitive only as channels do not open when membrane potential is more negative
- depolarizing - capacitive and gating as channels do open when membrane potential is less negative
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Term
| What is Threshold Potential? |
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Definition
- trick question: there is no true threshold potential
- the potential at which neuron reaches threshold varies widely between cells and at different times for same cell
- it is the rate @ which the potential changes that determines whether or not AP will occur
- this means that threshold relies on precise threshold current, not potential
- threshold's reliance on current is due to channel kinetics
- the faster the cell depolarizes(more positive inward current), the more likely it is for Nav current to outweigh the Kv current
- this is because Nav channels open more quickly than Kv channels despite responding to similar membrane potentials
- the faster the depolarization, the more pronounced the difference in channel kinetics become
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Term
| How do conductances affect AP and membrane potential? |
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Definition
- @ rest: gL is only non-zero conductance
- membrane potential stable @ Eleak=Vrest
- as Nav channels open, gNa becomes greater
- as Kv channels open, gK becomes greater
- membrane potential changes during AP are entirely dependent on balance between gNa and gK
- Overshoot: membrane potential exceeds reversal potential of 0mV
- due to gNa being much greater than gK
- ENa determines maximum peak of AP
- larger window of sodium entry = Vm getting closer to ENa or Vmax
- Undershoot: membrane potential falls below Vrest
- due to gK being much greater than gNa because of Nav channel activation and slow closing of Kv channels
- EK determines the lowest possible Vm
- larger window of potassium entry = Vm becoming more negative
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Term
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Definition
- absolute - stimulating another AP impossible
- Nav channels are inactive and cannot be stimulated by any depolarization event
- stimulation of another AP requires hyperpolarization so that Nav channels may become deactivated
- relative - stimulating another AP more difficult (need more stronger stimulus)
- not all Nav channels are recovered/deactivated; some are still inactive
- gK is still higher due to slow kinetics
- *depolarization of membrane is based on competition between gNa and gK, so higher gK makes it more difficult to reach threshold
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Term
| Stochastic Nature of Channels |
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Definition
- individual channels, such as nAch receptors, open randomly and their individual behavior is unpredictable
- however, we can determine the average behavior of a channel type (not specific channel)
- probability of being open
- mean open time
- important note:
- if Na current is present, both m-gate and h-gate must be open
- if Na current is not present, m-gate and/or h-gate may be closed
- position of gates must be inferred from membrane potential and time-course
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Term
| Cable Properties of Neuron |
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Definition
- AP propagation is active process, but relies on both the active and passive cable properties of the neuron
- dendrites
- exhibit passive cable properties
- do not contain (or contain minimal) voltage-gated channels to propagate graded potentials
- ions move through leak channels
- axon
- exhibits active cable properties
- ions move through voltage-gated channels
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Term
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Definition
- recordings of membrane potentials at different points of axon
- important as neurons are not spherical
- voltage changes decay over the length of the cylindrical axon
- electrotonic potentials decrease w/ increasing distance from stimulation site
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Term
| What important properties are provided through myelination? |
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Definition
- myelin acts as insulator
- effectively increases rm
- this increases λ = faster AP propagation
- more wrappings = greater resistance to current flow = faster AP propagation
- myelin decreases amount of open membrane thereby decreasing membrane capacitance
- less charge put on membrane in internodal regions
- faster conduction velocity
- no effect on internal longitudinal resistance
- decreases amount of energy required to maintain/repolarize cell to Vrest
- less membrane to repolarize/keep at rest
- less ATP required by Na/K ATPase
- conservation of energy
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Term
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Definition
- Schwann Cells in PNS
- wrap around axon directly
- one schwann cell/myelinated segment
- Oligodendrocytes in CNS
- wrap around axon using projections/legs
- one oligodendrocyte can myelinate multiple segments across multiple axons
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Term
| Do AP's jump during Saltatory Conduction? |
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Definition
- oversimplification: they occur in multiple nodes @ a time although peak will only be found in one node at a time
- As depolarization is spreading ahead and bringing next node to threshold, nodes “behind” the leading edge of depolarization are still active
- Therefore, conduction velocity is higher in myelinated and they can fire at higher frequencies than non-myelinated fibers
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Term
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Definition
- reliability of AP conduction measured by safety factor
- indicates ratio of depolarization produced by previous node to the depolarization required to bring next node to threshold
- amount of ΔV produced by AP that makes it to next node determined by passive cable properties of myelinated (internodal) segments of axon
- safety factor is 3-5 in normal adult mammalian axons
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Term
| How are voltage-gated channels distributed in myelinated axons? |
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Definition
- unmyelinated - more uniform distribution of Nav and Kv channels
- myelinated
- voltage-gated channels concentrated in nodes of ranvier
- Nav channels mainly concentrated in nodal region
- Kv channels mainly concentrated in paranodal regions
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Term
| How does demyelination affect channel distribution? |
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Definition
- neurons adapt to demyelination by spreading the distribution of voltage-gated channels (normally concentrated in and around nodes)
- w/in 21 days of demyelination, channel distribution is fairly homogeneous
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Term
| How does demyelination affect AP propagation? |
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Definition
- decreases conduction velocity
- frequency-related block - reduction in AP frequency, so that less signals reach terminal
- total block - total dissipation of AP, so that no signal reaches terminal at all
- ectopic impulse generation - random AP generation when there should not be
- increase in mechanosensitivity
- cross talk
- overall effects are slower, unreliable, or lack of conduction of APs and serious implications especially in event of signal block
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Term
| What is cross talk in terms of AP propagation? |
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Definition
- sometimes the propagation of an action potential through one axon can excite an adjacent demyelinated axon causing an action potential to propagate in both directions
- can result in ectopic impulse generation
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Term
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Definition
- characterized by patches of demyelination in brain and spinal cord resulting in multiple neurological symptoms
- autoimmune disorder in which nervous system attacks myelin sheathing in CNS (oligodendrocytes)
- T cells or B cells
- MHC genes have been linked to disorder
- can be caused by viruses
- viruses: mumps, measles, rubella, herpes viruses
- also caused by bacterial infections, dietary factors, exposure to animals, minerals, chemical agents, metals, organic solvents, and various occupational hazards
- symptoms
- weakness and clumsiness
- stiffness and gait disturbances
- visual defects
- mental defects
- lack of judgement
- emotional irritability
- sudden weeping or laughter
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Term
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Definition
- RRMS - relapsing-remitting
- most diagnosed
- short duration
- may remain symptom-free for long periods of time
- SPMS - secondary-progressive
- most w/ RRMS transition to this
- slow, steady progression w/ or w/out relapse
- relapses do not fully remit
- PPMS - primary-progressive
- steady worsening from start
- no periodic relapses or remissions
- PRMS - progressive-relapsing
- steadily worse from start
- flare-ups w/ or w/out remissions
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Term
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Definition
- Early symptoms
- numbness and tingling
- dizziness
- cognitive dysfunction
- fatigue
- vision problems
- depression
- walking difficulty
- and more
- often a diagnosis of exclusion - other diseases excluded to narrow it down to MS
- test include
- MRI
- electrophysiological test
- CSF exam
- evoked potential tests
- blood tests
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Term
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Definition
- limited remyelination may occur
- usually myelin comes back thinner w/ shorter internodes
- what provides the materials?
- oligodendrocyte precursor cells (OPCs)
- neural precursor cells (NPCs)
- stem cells
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Term
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Definition
- key compensatory mechanism for decreased conduction caused by demyelination
- demyelination brings the rm down and very few channels present under myelin
- partial recovery is upregulation of sodium channels in demyelinated segments
- partially restores conduction
- Nav1.2 channels are most common @ nodes of ranvier while Nav1.6 channels have much lower density
- Nav1.6 channels are upregulated @ nodes following demyelination
- Nav1.2 channels upregulated @ intermodal regions where myelin is no longer present
- there are dangers to this upregulation through interactions w/ Na/Ca exchanger
- high [Ca++]i results in cascade leading to cellular apoptosis
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Term
| Properties of Nav1.2 vs. Nav1.6 Channels |
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Definition
- Wexman study used voltage clamp to compare channels using mouse sensory neurons
- showed that Nav1.6 expresses higher amplitude of current indicating greater conductance gNa through these channels when compared to Nav1.2
- voltage dependence of activation and inactivation
- Nav1.6 channels show leftward (hyperpolarizing) shift compared to Nav1.2
- the 1.6 channels must be activated @ lower potentials
- activation @ lower potentials = threshold lowered (unless Kv channels also changed) =more Na entry
- voltage dependence of inactivation
- Nav1.6 channels show leftward shift compared to Nav1.2
- more 1.6 channels inactivated @ given voltage
- easier inactivation = less Na entry
- time-course of inactivation
- development
- inactivation more extensive and faster to develop for Nav1.6
- recovery
- slower to recover from inactivation
- lower frequency of APs possible
- resurgent Na+ current
- thought to provide the sub-threshold depolarization necessary to achieve high-frequency APs
- resurgent current has higher amplitude in Nav1.6 channels
- ability to maintain current amplitude during stimulus trains
- Nav1.6 channels maintains current amplitude better than Nav1.2 channels w/ stimulus train
- overall effect
- Nav1.6 activated @ lower potentials and better able to maintain high-frequency
- higher amplitude currents
- means more Na entry
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Term
| How can the channel upregulation compensatory mechanism hurt neurons? |
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Definition
- Nav1.6 channels are upregulated (as well as Nav1.2 channels in demyelinated regions) as compensatory mechanism for demyelination
- Nav1.6 channels are colocalized with Na/Ca exchanger
- excessive sodium entry, while helping to compensate for lesser conduction, builds up [Na]i
- high sodium entry near the exchanger results in exchange of sodium for calcium causing increase in [Ca]i
- higher [Ca]i can lead to cellular apoptosis cascade causing neuronal degeneration and further problems
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Term
| Nitric Oxide's Role in MS |
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Definition
- expression of iNOS (inducible nitric oxide synthase) increases @ site of MS lesions
- increased production of nitric oxide
- this puts stress on mitochondria
- results in dysfunction of mitochondria and ATP deficit
- cell has less available energy stores, but requires more than usual due to demyelination
- more stress is put on Na/K ATPase to repolarize more membrane due to more membrane exposed w/out myelin sheathing
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