20110104 Lecture 3 notes.txt

From Iusmphysiology

  • stareted here on 01/04 at 11AM


Contents

[edit] Review of lecture 3

  • Myelination makes signal transduction faster.

[edit] Learning Objectives

  • Understand the structure of an electrical synapse (the role of gap junctions)
  • Understand the structure of a chemical synapse
  • Understand the process for neurotransmitter release
  • Understand the sequence of events in the post­synaptic area
  • Understand the difference between direct and indirect type chemical synapses
  • Understand excitatory & inhibitory transmission (the importance of electrotonic conduction)

[edit] Neuron to neuron communications

  • There is a 50 nanometer area at the presynamptic space.

[edit] Gap junction {GJ) structure

  • There are vesicles at the synapse.
  • The gap junctions form channels by two connexon hemichannels.
    • One channel is each of the two cells of the synapse.
    • They are tightly glued together by molecular forces.
    • No ions can flow between the channels.
    • So this is a small, permeable, channel between the two cells.
    • The AP flows through these gap junctions.
  • Gap jxns are regulated by calcium;
    • Closed when Ca is present, open otherwise.
  • The gap jxn channels are made of 6 subunits, called connexins.
    • Each connexin has four transmembrane domains.

[edit] A chemical synapse

  • The vesicles at the synapse contain neurotransmitters.
  • Voltage gated calcium channels open when the AP arrives.
  • Ca rushes in and causes vesicles to be released at the membrane.
  • The released NTs cause reaction of the post-synaptice cell.

[edit] Type of synaptic vesicles

  • Clear vesicles, 40 to 50 n m in diameter, that appear empty on electron micrographs (anchored to cytosceleton, contain acetylcholine, glycine, gaba, glutamate)
  • Dense core veiscles:
    • 100 nms
    • dense on EM
  • Large dense-core secretory granules
    • Up to 200 nm
    • Store signaling peptides, hence their size.

[edit] Synaptic vesicle fusion

  • There are 30-50 proteins important for synaptic vescicle fusion, we'll just highly 5 or 6.
  • Ca2+ BS is important for detecting the concentration of CA.
  • Synaptobrevin is important for docking of pre-synaptic membrane.
  • Syntaxin-1 and Snap25 are important for interaction with presynaptic membrane.
  • NSF is the most important for regulation.
    • Has an orange inhibitory domain.
    • Is bound by munc18 which keeps NSF closed and silent and therefore keeps the vesicle from releasing.
    • When Ca is high, a bundle of four helices is generated to form a zipper.
    • Two helices from SNAP25, one from syntaxin-1 and one from synaptobrevin form a zipper which then slides the two membranes together to release contents.
  • There are two cases of pore formation:
    • Short term version which opens the form for a short time such that it can be reused 
Name
    • Long term version such that the vesicle is full fused w/ membrane.

[edit] The motor end plate

  • A-alpha fibers
    • Big (10 mm), fast (up to 120 m/sec)
    • Usually multipe fibers innervated by one nerve.
  • The motor plate is the interface of the neuron and the nerve.

[edit] Neuromascular junction (motor end plate)

  • The AP stimulates voltage-gated Ca channels.
  • Ca increases above a threshold.
  • The predocked vesciles release their NT (acetylcholine).
  • AcH difuses to post-synaptic and stimulates.
    • The receptors are well situated directly across from the pore release location on pre-synaptic.
  • We then clean up the ach so the muscle can relax.
    • Ach esterase cleaves ach to form choline and acetate.
  • A proton exchange pump brings Ach back into the pre-synaptic cell into the cytoplasm.

[edit] Acetylcholine receptor-channel

  • The acetylcholine nicotinic receptor is a ligand gated channel.
    • The ligand is ach itself.
    • This channel is non-specific so it passes any positively charged ion because it has several negatively charged aa in it's channel domains.
  • GABA is another important channel.
    • These are chloride channels.
    • They have positively charged residues in their pore.

[edit] Post synaptic stimulation result

  • Na and Ca rush into the muscle cell
  • More Na channels are opened by this voltage change.
  • When Na and Ca change potential above threshold, the muscle fibers themselves will help generate an AP.
    • This will happen by Ca influx by way of voltage-gated channels and the Ca store in the sarcoplasmic reticulum.


[edit] lonotropic versus metabotropic chemical synapses

  • We just talked about direct chemical synapse.
  • There are also indirect chemical synapses.
  • We can increase our heart rate, for example, without using neuro jxns but chemical signals like epinepherine.
  • In cardiomyocytes there are no nicotinic receptors but we can stimulate musculinic receptors with epinepherine.
  • Musculinic receptors activate g-protein receptors.
  • Musculinic receptors in this case activate K+ channels that move K+ into the cell and polarize, potentially hyperpolarizing it.
    • This causes the hear to beat more slowly.

[edit] Synapse types

  • Ionotropic receptors use a neurotransmitter: Ach which stimulates nicotinic receptors
    • Works very rapidly (1 ms)
  • Metabotropic receptors use Ach, also and stimulate muscarinic receptors (which are g-proteins).
    • has several minutes of delay while the g-protein works and the effector proteins are affected (kinases, phosphatases, etc.)
  • Direct electrical transmission of AP needs no transmitter
    • This is the fastest, less than 0.1 ms delay.

[edit] Comparison of electrical and chemical synapses

  • Electrical synapses:
    • These work like resistors: they decrease the original signa.
    • These are usually bidirectional; that is, the signal will spread both directions from the receptor of the NT.
      • This is good for synchronizing neuronal networks because it can split the signal.
    • These block high threshold signals.
    • These are important for basic function of all nueronal systems because it glues the pre-and-post membranes together so that chemical synapses work.
      • In fact, the neuronal system doesn't develop correctly without electrical synapses.
  • Chemical synapses
    • Slow
    • Amplify the signal
    • Easy to manipulate
      • For example, simple use of a kinase can phos a Ca+ channel and stop or start synapsing.
      • This is important for memory.

[edit] The most common synaptic arrangements in the CNS

  • Dendrites have small outpockets in the membrane called spines.
    • These are very dynamic in their growth and deminishment.
    • This may be a form of memory.
    • This can help inhibit the synaptic strength by decreasing spines.

[edit] Ribbon synapses

  • We need to be able to flexible in our synapse powers of our muscles because we use them and then we don't.
  • The retina and hair cells, however, are always firing.
  • So how do we keep them functional for constant use?
    • Ribbon synapses.
  • Ribbons = disks
  • The ribbons tether the synaptic vesicles on the surface of the membrane so several vesicles are docked and ready to release NT.
  • Then kinsein is a motor used to deliver the next vesicles for release of NT.

[edit] Gaseous neurotransmitters

  • NO is an example.
  • NO is produced in a Ca-dependent manner, too.
  • NO synthase increases activity when Ca+ increases.
  • NO can be immediately degraded via oxidation, but if not, it diffuses through membrane of pre and post synaptic cell.
  • It then stimulates adenylyl cyclase which activates PKG (a cyclase sensitive kinase).
  • The post synaptic cell can also generate NO to signal to the presynaptic cell and regulate it's activity.

[edit] Synthesis and recycling of synaptic vesicles and their content.

  • How do we replenish the proteins used for vesicle fusion, etc. at the distal end of the neuron?
    • This includes mt because we need energy to do all this.
  • We have an axonal transport mechanism.
  • The rate of vesicle transport is about 0.5 meters / day, though the mt take longer because they are larger.
  • There is anterograde and retrograde.
    • Anterograde is faster

[edit] Molecular motors move the vesicles along the axon using the energy of ATP

  • Kinesin is important for anterograde transport.
  • Dynein is important for retrograde transport.
  • Microtubules are the tracks for kinesin and dynein.

[edit] Spiking patterns

  • Gaps occur because ca-sensitive k channel is activated.
    • This isn't the only mechanism for modulation, though.
  • A second way to modulate spikes is to inhibit synapsing.

[edit] Modulation via synapse modulation

  • Modulation can occur by summation, spacial separation of synapsing, or temporal summation of the AP.

[edit] Attentuation of EPSPs in Dendrites

  • How do we select among two simultaneous APs?
  • The dendrite thickness can affect how well an AP is transduced and therefore may affect which signal causes threshold changes.
  • A neuron can grow a thicker dendrite for a preferential AP route.

[edit] Interplay of inhibitory and excitatory inputs

  • Inhibitory synaptic signals can also occur; these cause hyperpolarization which keeps the neuron from being depolarized as easily.

[edit] Types of synaptic plasticity

  • Facilitation: temporary increase in the EPP / PSP because of high frequency of stimulation
  • Potentiation is a long-lived increase in NT release because of high frequency stimulation
    • Usually because of a buildup of Ca in the terminals such that docking is prolonged and NT release increases.
  • Synaptic depression: short term decrease in synaptic transmission because of high frequency of signaling and lack of NT / vesicles
    • Could be from low concentration fo NT in vesicles.
  • Habituation: long term, slow onset decrease in synaptic transmission because of low stimulation frequency
    • usually by way of separation of AP by space or time.

[edit] Types of synaptic plasticity

  • Ca is important for potentiation

[edit] Diseases associated with synaptic transmission dysfunctions

  • Myasthenia gravis-autoimmune
    • An antibody is formed against the nicotinic receptors.
    • This causes autoimmune attack.
    • This causes desensitiation of the receptors such that picking up a chair works the first time but not the second.
  • The Lambert-Eaton syndrome-autoimmune,
    • antibodies against the presynaptic Ca2+ channel (in the limb muscles)

[edit] Pharmacological tools modulating synaptic

  • Pyridostigmine
  • DFP
  • Both inhibit acetylcholine esterase
  • This increases concentration of ach to increase post-synaptic stimulation.

[edit] Botox

  • Used to treat spacpicity and for cosmetics
  • The toxin stop the functions of the proteins in fusion, such that there is no relase of NT.
  • Called BNT-A,c,e
  • Clinical use of myobloc (BoNT type B) to treat cervical dystonia, strabismus, and spacticity.
    • This cleaves synaptobrevin

[edit] Summary

  • stopped here on 01/04 at 12PM
Retrieved from "http://editthis.info/iusmphysiology/20110104_Lecture_3_notes.txt"
Personal tools