20110104 Lecture 3 notes.txt

From Iusmphysiology

• stareted here on 01/04 at 11AM

Contents 1 Review of lecture 3 2 Learning Objectives 3 Neuron to neuron communications 4 Gap junction {GJ) structure 5 A chemical synapse 6 Type of synaptic vesicles 7 Synaptic vesicle fusion 8 The motor end plate 9 Neuromascular junction (motor end plate) 10 Acetylcholine receptor-channel 11 Post synaptic stimulation result 12 lonotropic versus metabotropic chemical synapses 13 Synapse types 14 Comparison of electrical and chemical synapses 15 The most common synaptic arrangements in the CNS 16 Ribbon synapses 17 Gaseous neurotransmitters 18 Spiking patterns 19 Modulation via synapse modulation 20 Attentuation of EPSPs in Dendrites 21 Interplay of inhibitory and excitatory inputs 22 Types of synaptic plasticity 23 Types of synaptic plasticity 24 Pharmacological tools modulating synaptic 25 Botox 26 Summary

Review of lecture 3

• Myelination makes signal transduction faster.

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)

Neuron to neuron communications

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

===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

===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.

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.

Modulation via synapse modulation

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

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.

Interplay of inhibitory and excitatory inputs

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

Types of synaptic plasticity

*FAcilitation:

• Potentiation makes the AP last longer.
  • Usually because of a buildup of Ca in the terminals such that docking is prolonged and NT release increases.
• Synaptic depression
  • Could be from low concentration fo NT in vesicles.
• Habituation
  • usually by way of separation of AP by space or time.

Types of synaptic plasticity

• Ca is important for potentiation

===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)

Pharmacological tools modulating synaptic

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

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

Summary

• stopped here on 01/04 at 12PM