Physio Action Potential & Synaptic Signals (4/5)

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  1. Lecture 4 - Action Potential Generation & Conduction
  2. Depolarization & Repolarization
    • Depolarization (upshoot): Na+ channels are open, K+ channels are CLOSED

    • sodium (+ charge) rushes into a cell, depolarizing the membrane, making it more positive inside 

    • Repolarization (downshoot): K+ channels are OPEN, Na+ channels are closed

    • to return the membrane to its normal (negative) resting potential, POTASSIUM (positively charged) exits the cell through open channels - too much, in fact, leaves, causing hyperpolarization b/c K+ channels are slow to close
  3. Voltage-dependent Sodium & Potassium Channels
    channels that can be open and shut depending on membrane potentials
  4. What is the overshoot of an action potential dependent on?
    • ENa
    • if you change the Na+ concentration outside the cell (eg. make it LESS concentrated) the peak of the action potential will DECREASE
    • Image Upload 1
    • when a membrane is signaled, Na-gated channels open much more quickly than K-gated channels → depolarization (action potential)
  5. What is the undershoot of an action potential dependent on?
    • EK
    • increasing [K+] outside makes EK more positive & makes the undershoot MORE positive
    • K-gated channels open much more slowly than Na-gated channels → re-polarization
    • then hyperpolarization (pulled almost down to EK) b/c they're also slow to close
  6. Conformational States of Na+ Channels
    • 1. closed but available to open in response to membrane depolarization
    • 2. open
    • 3. closed & unresponsive to membrane depolarization
    • depending on the membrane voltage, the channel can transition from one state to another
    • Image Upload 2
  7. Inactivated State
    • the state in which an Na+ channel is closed & unresponsive to membrane depolarization
    • mutating a stretch of hydrophobic residues eliminates inactivation, allowing channels to stay open for as long as the depolarization lasts, which can lead to a number of human disorders
  8. Channel Permeability
    • PNa: begins early & then inactivates
    • PK: begins more slowly & then does NOT inactivate
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  9. The Hodgkin Cycle
    • describes the regenerative increase in the number of open Na+ channels & why an action potential initially occurs
    • a positive feedback loop in which an initial membrane depolarization leads to an uncontrolled rise in the membrane potential close to ENa
  10. Refractory Periods
    b/c the Na+ channels become inactivated & the K+ channels take a while to close again after the action potential has occurred, there's a natural upper limit to the rate at which a nerve cell can generate action potentials
  11. Relative Refractory Period
    • action potential is smaller (reaches a lower depolarization value than normal) & requires a higher voltage stimulus to initiate the depolarization
    • usually doesn't happen in nature, just seen during experiments
  12. Absolute Refractory Period
    • the period immediately following the firing of a nerve fiber when it CANNOT be stimulated no matter how large a stimulus is applied
    • there's a strict upper limit with which one can get an action potential out of a neuron
  13. What type of conduction do dendrites use?
    • passive conduction b/c they're not very long
    • however when conducting a signal down an axon only voltage-gated channels will work (need an amplifier)
  14. What happens if you trigger an action potential in the MIDDLE of an axon? At "two ends" of an axon?
    • if a laboratory axon is stimulated in its middle, both halves of the axon are "fresh", unfired
    • therefore 2 action potentials will be generated: one travels toward the axon hillock & the other travels towards the synaptic cleft
  15. What happens if you trigger an action potential at "two ends" of an axon?
    they will propagate until they meet (in the middle) and then will no longer be able to continue as Na+ channels will be unable to open as they're in their refractory period
  16. What determines the speed with which an action potential can be propagated?
    • conduction velocity is a function of the LENGTH CONSTANT
    • an axon with a larger diameter has a lower internal resistance & therefore a LARGER length constant
    • therefore conduction velocity by way of relation to length constant is related to axon diameter
    • larger diameter axons conduct action potentials more rapidly
  17. What does insulating an axon do?
    • increases the length constant → conducts action potentials more rapidly
    • myelin is produced by oligodendrocytes in the CNS & schwann cells in the PNS
  18. Nodes of Ranvier
    • where action potential occurs b/c they're where voltage-dependent Na+ channels are located
    • internode: portions of the axon insulated with myelin (millimeters long)
  19. Multiple Sclerosis
    • a demyelinating diseases in which nerve myelin degenerates decreasing the ability of a nerve to conduct action potentials
    • Na+ channels are still localized to old nodes, but the absence of myelin exposes the K+ channels to the outside
    • Na+ current generated at a node will flow into the demyelinated membrane & depolarize it, but b/c there aren't Na+ channels present in the newly exposed membrane, it is unable to regenerate the inward current necessary for continued action potential generation → action potential fails to propagate
    • the length constant of such an axon decreases a lot
  20. Cardiac Stimulation
    • voltage-dependent Ca2+ channels cause a prolonged action potential during which the heart muscles continually contract in order to pump blood
    • K+ & Ca2+ permeabilities exhibit a similar time course but have OPPOSITE effects on the membrane potential b/c they carry current in opposite directions → generates a plateau on the falling phase of the action potential during which K+ & Ca2+ currents are ~equal in magnitude but opposite in direction
    • cardiac muscle APs last ~300 ms longer than those of skeletal muscle
    • Image Upload 4
  21. How much of the genome is devoted to coding for ion channels?
  22. Hyperkalemic Periodic Paralysis (HPP)
    • a rare autosomal dominant disorder caused by mutations in voltage-dependent Na+ channels gating
    • Na+ channels fail to inactive & stay open longer than normal
    • involves episodes of muscle weakness & sometimes higher than normal levels of K+ in the blood
  23. HPP Symptoms
    • acute, transient paralysis in limbs & trunk muscles due to loss of muscle excitability
    • attacks increase during rest after exercise & patients are often asymptomatic between attacks
  24. 5 Synaptic Signals
  25. Is there electrical transmission at synapses?
    • NO - almost never
    • (exception = gap junctions for very high speed transmission)
  26. How are presynaptic and post synaptic cells connected?
    virtually all synaptic transmission is mediated chemically via the release of chemical (neuro)transmitters by Ca2+ controlled exocytosis
  27. What are two potential problems with chemical transmission across synapses?
    • 1. slowing of information - the nervous system just deals with it (only takes an extra 0.2 milliseconds)
    • 2. potential non-synchronous vesicle release - nature has evolved a mechanism to make sure transmitters are exocytosed at the same time
  28. When does Ca2+ need to be present during synaptic transmission?
    • has to be supplied RIGHT when the action potential arrives at a neuronal or neuromuscular junction
    • if Ca2+ is applied before or after the action potential, there is no response from the receiving entity
  29. Is Ca2+ present only extracellularly, outside the nerve terminal or does it go into a nerve terminal?
    Ca2+ has to enter the presynaptic terminal during the action potential in order for vesicle release to occur
  30. What is the relationship between amount of Ca2+ that enters the pre-synaptic cell & synaptic response of the post-synaptic cell?
    • as you increase the inward Ca2+ current, the post-synaptic response gets larger but in a VERY non-linear way (the synaptic response increases nonlinearly with increases of Ca2+ concentration)
    • suggests multiple Ca2+ ions are needed to release a synaptic vesicle
  31. How is transmitter released? As single molecules of transmitter?
    • release of transmitters occurs when vesicle membrane fuses with the pre-synaptic cell's plasma membrane
    • the SMALLEST response you can get out of a synapse is the release of transmitters from an entire vesicle (~10,000 molecules)
  32. End-plate Potential (EPPs)
    the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction
  33. Miniature End-plate Potentials (MEPPs)
    the small (~0.5mV) depolarizations of the postsynaptic terminal caused by the release of a single vesicle into the synaptic cleft
  34. How are neurotransmitters pumped into newly formed synaptic vesicles in a neuron's cytoplasm?
    • via an energy dependent process
    • a vacuolar ATPase burns ATP to pump H+ ions into the vesicle, creating a low-pH environment
    • that H+ ion gradient drives the process of loading transmitters into the vesicle
  35. What happens after neurotransmitters are loaded into a synaptic vesicle?
    it is then translocated to & docked at the presynaptic plasma membrane via SNARE proteins
  36. SNARE proteins
    proteins involved in keeping synaptic vesicles plastered up against/attached to the presynaptic plasma membranes
  37. v-SNAREs
    • membrane proteins in a budding VESICLE that are responsible for fusion of the vesicle with the correct target membrane
    • v for vesicle
    • are cognate to t-SNAREs
  38. t-SNAREs
    • membrane proteins in a cell or organelle PLASMA MEMBRANE that facilitate the fusion of the target membrane with the correct vesicle
    • t for target
    • are cognate to v-SNAREs
  39. SNAP25d
    • a t-SNARE & cytoplasmic molecule that complexes with synaptobrevin (SV membrane) & syntaxin (plasma membrane) to attach an exocytotic vesicle to the plasma membrane
    • Image Upload 5
  40. What effect does Clostridium botulinum have on SNARES?
    • deadly neurotoxins produced by the anaerobic bacterium can hydrolyze snares, blocking exocytosis causing muscle paralysis, respiratory failure, & death if untreated
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  41. The step that primes the vesicle for fusion with the plasma membrane is unknown
    it's known that said step requires energy, as the fusion of two lipid membranes is an energetically unfavorable process
  42. Synaptotagmin
    • a protein found in the synaptic vesicle that prevents (or greatly reduces) spontaneous fusion of the vesicle & plasma membrane
    • acts as a fusion brake under resting conditions
  43. How does Ca2+ influx into the nerve terminal promote exocytosis of the contents of synaptic vesicles?
    after Ca2+ influx into the nerve terminal, each of synaptotagmin’s two lobes bind Ca2+, promoting a conformational change that releases the brake on the core complex & promotes membrane fusion → releasing NTs across the synapse
  44. After releasing NTs across the synapse what happens to the vesicle?
    • it's recycled (because it already has a lot of valuable proteins set up within it) via a clatharin coat that facilitates it pinching-off from the plasma membrane
    • it then fuses with an endosome & from there is pinched off when a new vesicle needs to be formed
  45. A postsynaptic response is:
    NOT an all or none response - the strength of the presynaptic signal determines a response?
  46. What entities are highly concentrated at the neuromuscular junction?
    ACh receptors - makes it more convenient & speeds up the information transmission time
  47. What is one marked difference between voltage-gated & chemically gated ion channels?
    • chemically gated channels are often permeable to multiple ion species (unlike voltage-gated ion channels)
    • is especially true for cation channels (b/c Na+ & K+ have the same valence, unlike Cl- channels, b/c few other ions have that valence)
    • eg. ACh receptors at the NMJ
  48. For the ACh receptor at the NMJ, how is the permeability for Na+ related to the permeability for K+?
    • the permiabilities are approximately equal
    • PNa ~ PK
    • based on this the amount of ion flux for each should be the same
  49. Why is the fact that the ACh receptor at the NMJ is equally permeable to Na+ & K+ not a problem for synaptic transmission?
    • because the normal resting potential is very close to the resting potential for K+
    • if you open a channel permeable to K+ & Na+, there's no gradient/electrochemical driving force to facilitate the movement of K+ into a cell
    • therefore Na+ is really the only thing that moves
  50. At the normal resting potential, the inward Na+ current is much _______ than the outward K+ current
    • the inward Na+ current is much LARGER than the outward K+ current
    • INa >> –IK
    • Image Upload 7
  51. What would ion movement through a channel look like if a cell's membrane potential (Em) was positive (as opposed to the usual negative)?
    • when Em is POSITIVE, the outward K+ current is much larger than the inward Na+ current
    • INa << –IK
    • Image Upload 8
  52. Reversal Potential
    in the case of post-synaptic neurons, it's the membrane potential at which a given neurotransmitter causes NO net current flow of ions through that neurotransmitter receptor's ion channel
  53. Why aren't ion channels highly selective & permeable only to Na+ to streamline the formation of postsynaptic action potentials?
    • because it's difficult to form a channel selective for ONE type of cation
    • it's difficult for a molecule to differentiate between Na+ & K+
  54. How do you stop a synaptic response at a muscle fiber?
    • AChase (ACh esterase, AChE) is located in the synaptic cleft
    • terminates the synaptic response at the NMJ by degrading ACh → choline + AcetylCoA
    • terminates the muscle response really quickly
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  55. What type of ion channels are stimulated to open during an inhibitory neuronal signal?
    • Cl- channels = inhibitory signals
    • Cl- flooding into a cell reduces the tendency for a neuron to produce an action potential (keeps the Em low; the Nernst potential for Cl- is low near EK)
  56. Which neurotransmitter commonly opens Cl- channels?
    • GABA (γ-aminobutyric acid) - a modified glutamate
    • sometimes the AA glycine (uses different receptors than GABA though)
    • Image Upload 10
    • what an inhibitory response looks like
  57. Normally, ECl is more _________ than the resting potential (Erest)
    • NEGATIVE: ECl << Erest
    • when Cl- channels, opened by GABA, move Em away from threshold causing inhibition
    • the KCC2 active pump, which uses ATP to move K+ & Cl out of the cell, increasing the Cl- concentration gradient (b/c Cl- is normally low inside a cell) FURTHER lowers the Em (membrane potential)
    • Image Upload 11
  58. NKCC1
    • an ion pump active during development that works in the opposite way the KCC2 pump works
    • it pumps Na+, K+, & Cl- INTO the cell, causing ECl to be above Erest & Ethreshold
  59. What happens when KCC2 is blocked & NKCC1 is active?
    • ECl is more POSITIVE than Erest
    • therefore during development opening Cl- pathways may be excitatory
    • in addition, this means that inhibitory pathways in adults may be excitatory pathways during early development
    • Image Upload 12
  60. What is the relationship between epilepsy & seizures and GABA?
    • benzodiazepines are drugs used to treat epilepsy, & do so by enhancing the effect of GABA
    • because seizures are uncontrolled firing of neurons, inhibiting such uncontrolled firing using said GABA agonist helps treat the disease
  61. In what subset of epileptic patients would treatment with benzodiazepine worsen their seizures?
    • in patients who have an active NIKCC1 pump but an inactive KCC2 pump
    • the GABA agonist opens Cl- channels, however in these patients, this process results in an excitatory (as opposed to normal) inhibitory response
  62. G protein-coupled (Metabotropic) Receptors
    • a type of membrane receptor that acts through a secondary messenger
    • they're indirectly linked to ion channels on the plasma membrane of the cell through signal transduction mechanisms, often G proteins
    • such responses are much SLOWER & last LONGER than those modulated by an ionotropic receptor
    • not all ion channels that modulate neuronal activity respond directly to the binding of a NT
    • Image Upload 13
  63. What's an example of a signal relayed via metabotropic receptors?
    the effect of ACh on heart muscles - causes a slowing on the heart rate because it works on metabotropic receptors
  64. How is synaptic strength variable?
    • • by the location of synaptic site relative to spike initiation zone
    • • depending on the amount of quantal content (NTs) released during a stimulatory or inhibitory event
    • • postsynaptic receptor density (# of receptors is under tremendous regulation depending on how often signals are received)
    • • passive properties of the postsynaptic membrane
    • • the number of postsynaptic voltage-gated channels (the more there are the greater the responses)
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Physio Action Potential & Synaptic Signals (4/5)
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