1
Q
Origin of nervous system
A
- hypothetical multicellular organism with sensory cells controlling motor cells by releasing a chemical transmitter into the fluid space
- direct connection between the cells via a nerve axon means communication is quicker and more specific
2
Q
Diffucsion
A
- time for a molecule to travel a distance is : t = x^2/D
- D is the diffusion coefficient (larger = molecular movement is higher)
- value is determined by the velocity of the molecule and the mean collision time
- diffusion increases quadratically with distance
3
Q
Stokes Einstein Law
A
- time taken for diffusion is proportional to the square of the distance travelled
4
Q
Motor Proteins
A
- still too slow for the nervous system: need for electrical signalling
- long axons are problematic
5
Q
Actin
A
**
6
Q
Microtubule
A
- highways in axons for motor proteins to walk bidirectionally carrying cargo
- needed for neuronal function
7
Q
Classical Neuron
A
- uses electrical signalling
- chemical transmission at synapses
- dendrites recieve signal that propogates through the soma, down the axon, and into the synapses
8
Q
Why are membrane channels needed
A
- moving a charge from water to lipid costs a lot of energy (about 338kJ/mol)
- the membrane presents an energy barrier to ion crossing: energetically unfavorable
- ion movement sets up a potential difference in voltage (energy gradient)
- by discharging in a controlled way via channels we can harness this energy
9
Q
Active pumping
A
- pumps maintain ionic concentration differences
- usually use ATP for energy
10
Q
Sodium Potassium ATPase
A
- key pump in maintaining membrane potential at rest
- drives ions against electrochemical gradient
- 2 K in and 3 Na out using ATP
11
Q
Ion Distribution Across Neuronal Membranes
A
- resting voltage is -60/-75 mV
- 140 mM K inside and 3 mM outside
- 15 mM Na inside and 130 mM outside
- other ions like Ca or Cl also contribute
12
Q
Equilibrium Potential
A
- consider bath separated by membrane permeable only to K ions
- high concentration of potassium salt is introduced into one side and low concentration on the other
- K ions diffuse down the gradient to one side giving an excess of positive charge on the right hand side of the membrane and an electrical potential difference
- each time K moves across the membrane it leaves a negative charge on the left side
- eventually an eq. potential is reached where the chemical force = the electrical force
13
Q
Nernst Equation
A
- calculates the membrane potential of any ion with differential concentration across the membrane
14
Q
Channel Opening
A
- all kinds of stimuli can open channels including voltage, ligand binding, mechanical force, and temperature
- energy (voltage) is discharged by selective opening
- membrane is a capacitator (insulator separating 2 areas of charge)
15
Q
Signalling Information in Neurons
A
- done via changes in membrane potential
- sharp changes: action potentials
- graded changes
- voltage changes causes channel proteins to change shape and conduct ions across the cell membrane/shut channels
- also allows calcium ion entry to promote vesicle fusion and transmitter release
- essentially, a change in electrical energy causes a protein shape change due to charged residues
- this is a form of communication
16
Q
Depolarisation
A
- becomes more positive (increase)
- reduction in difference of electrical potential across the plasma membrane of a nerve or muscle cell
- usually excitatory
17
Q
Hyperpolarisation
A
- more negative inside cell (decrease
- increase in difference of electrical potential across the membrane
- usually inhibitory
18
Q
Space Constant
A
- when the axon length is equal to the space constant, the signal decays to 37% of the original signal
- short axons don’t need action potentials because of this
- voltage decays exponentially and may or may not be enough to trigger a signal at the synapse
- typically 0.1/2 mm in nerve fibers
- look at equations *
19
Q
Solution to Space Constant
A
- myelin and action potentials, ie. better axon insulation
- experiment: when current is injected at one point in the axon, voltage change can be measured at different points via electrodes. In mammalian axons, the depolarization spreading to the adjacent region of the axon is still above the threshold. Thus, a full action potential is generated at each point in the axon.
20
Q
Myelination
A
- formed by glial cells creating a high resistance low capacitance sheath
- increases the space constant and the action potential jumps from node to node (increasing speed)
- gaps are Nodes of Ranvier
- myelinated axons: propogration not a wave but a slower jump
- slower due to channel opening
21
Q
All or None Effect
A
- positive feedback
- voltage change changes membrane permeability to sodium causing a positive voltage change
- triggers rapid depolarization
- above a certain threshold triggers this potential
o All or none: if depolarization is above the threshold the action potential is determined by the ion concentrations
o Three properties: all or none, regenerative, and unidirectional
22
Q
Rate of AP
A
- frequency/rate of firing encodes information
23
Q
Phases of teh Action Potential
A
- depolarization phase (+30mV) from resting potential (-75 mV)
- repolarization phase where sodium channels inactivate and potassium channels open
- undershooting (relative refractory phase) where potassium is overactive before returning to eq.
24
Q
Understanding the Action Potential
A
- after reaching threshold, sodium conductance increases quickly but inactivation then reduces the conductance to 0
- potassium conductance increases slowly and decreases after hyperpolarization
- absolute refractory period: inactivation of sodium channels
- relative refractory period: potassium conductance dominates following action potential
25
Voltage Clamp
- K currents activate following depolarization but show little inactivation
- Na current governed by two kinetic processes activation and inactivation following depolarization
- both channels deactivate during hyperpolarization
26
Process of Action Potential
1. at rest there is a small resting potassium permeability through voltage independent leak channels (leak K channels)
2. during the up shoot of the AP voltage gated Na channels open increasing Na permeability of the membrane
- the more channels open the more Na channels open in positive feedback response
3. repolarization of AP involves sodium channel closure (inactivation and depolarization) and the activation of voltage gated potassium channels
- K channel opens via ball and chain mechanism: when membrane potential is positive there is repulsion of charged residues opening the channel
- repolarization occurs due to outward flow of K ion
4. refractory period persists until the voltage gated sodium channels have recovered from inactivation
5. ionic gradients are re-established by ATPase activity
27
AP propagation
- speed of the action potential depends on how far the passive depolarisation spreads
- this is determined by the space constant and membrane capacitance
28
Multiple Sclerosis
- autoimmune destruction of myelin surrounding the nerves of the central nervous system leads to a progressive burden of neurological deficits
- caused by poor and less efficient nerve conduction
29
Ion Channel Structure
- all channels from the same gene superfamily
| - related structures
30
Voltage Gated Sodium Channel
- single protein with 4 TM forms channel
- both termini on the inside
- 2000 amino acids
- each of the 4 domains have voltage sensor of positive residues that move when voltage changes
- selectivity filter: strips hydration shell using perfect shape and complementary interior residues
* read more *
31
Voltage Gated Potassium Channels
- Channel comprises 4 subunits each with 6 helices. The first four helices are the voltage gated sensors and the last two helices form the pore domain with the selectivity filter.
Ball and Chain model: cytoplasmic portion of channel protein (ball) blocks opening during refractory period. Depolarisation also causes movement of charged residues to create a negative pore to facilitate positive ball entry
32
PassingInformation between Neurons
1. gap junctions: electrical transmission
- bidirectional, fast, nonspecific
- signal decay means the voltage change is low
2. chemical transmission
- unidirectional, integrative, regenerates signal
33
Neuro-Transmission Trigger
- action potential moves down axon terminal and opens voltage gated Ca channel
- Ca binds proteins causing shape change and vesicle release
- Calcium entry is excitatory and depolarizes the membrane
- also second messenger
34
Vesicle Synthesis
- clathrin mediated endocytosis of vesicle from membrane and filling of vesicle
- vesicle docking and priming
- either full fusion or kiss and run recycling
35
Chemical Neurotransmission Process
1. transmitter synthesis in presynaptic neuron
2. storage in presynaptic nerve terminal
3. release of transmitter into cleft
4. binding and recognition by target receptors
5. termination of action (recycling, degradation)
36
Vesicle Fusion
- fusing naked vesicles with other lipid membranes would require substantial energy
- SNARE mechanism
- each SNARE pin releases about 35 kbT of energy as it zippers
- the activation energy for lipid bilayer fusion is about 50-100 kbT
- provides enough energy to drive fusion
37
SNARE Proteins
1. synaptogamin: calcium sensing protein
2. synaptobrevin
3. syntaxin
4. SNAP-25
- trihelical bundle
38
Calcium dependent vesicular release
- vesicle docks
- SNARE complex forms to the pull membrane togethr
- calcium binds synaptogamin
- calcium/synaptogamin catalyzes membrane fusion by binding to SNAREs and the plasma membrane
- protein shape change pulls membranes together
The mechanism through which Ca2+ induces synaptic vesicle exocytosis is beginning to come into focus. The major Ca2+ -sensing protein appears to be synaptotagmin I, a protein with a single helix passing through the synaptic vesicle membrane, whose cytosolic domain contains four Ca2+ binding sites. At resting levels of Ca2+, synaptotagmin I binds to the Q-SNARE syntaxin (Section 12-4Db) so as to block its binding to the R-SNARE synaptobrevin and the Q-SNARE SNAP25, thereby preventing vesicle fusion. However, on binding Ca2+, synaptotagmin I releases syntaxin, permitting vesicle fusion to commence.
39
Synaptogamin
o Calcium sensor with binding sites
o Regulates release of vesicles
o Releases inhibitory clamp of complexin
o Complexin clamps the vesicle at in intermediate step
o Cooperative binding of calcium ensures there is transient and local activation
o Calcium channels bind to 2 active zone core components including a GTPase
o This brings the vesicle close to the channels and supports the cytoskeleton
o Other adhesion molecules bring the two plasma membranes of the neurons together
o RIM protein complex binds to the channel and the vesicle via Rab 3
40
Graded Signals
- Graded potentials possible – information is graded (?)
| - Graded signals release more/less transmitter
41
Information of Signaling
- Frequency of action potentials / quantity of neurotransmitter
- Diversity of neurotransmitters triggered??
- Action potential only describes that a signal is transmitted not what kind of signal is transmitted
- Exceptions in very short or non-myelinated neurons
- Frequency of action potentials / quantity of neurotransmitter
- Diversity of neurotransmitters triggered??
- Action potential only describes that a signal is transmitted not what kind of signal is transmitted
- Exceptions in very short or non-myelinated neurons
42
Saltatory Conduction
- ‘Jumping’ of action potential from Node of Ranvier between myelin sheath
- Ensures action potential/signal propagates over longer distances
- To do with speed of transmission from point A to point B. Two factors govern speed of spread: velocity = length constant / t (membrane time capacitance)
- Membrane capacitance: capacitance across membrane governs voltage change speed across membrane
- Action potentials evolved to regenerate decay of voltage over length. Myelin greatly increases lamda (space constant) but net effect on t is not much if you add myelin.
- With myelin the currents are going longer distances without decaying (as opposed to local currents without). Myelin increases conductance velocity (as well as diameter): spread is speedier.
- Jumping slows it down as in order to regenerate action potential at the nodes (like a pit stop). It is also energy efficient as you need less ATP pumps
- V = lamda / -1 x t x T (time to open channels, about a millisecond)
43
Dense Core vesicles
- Stores and releases neuropeptides via exocytosis. Filled at the Golgi network and transported down the axon to synapses. Peptide neurotransmitter molecules and biogenic amines like dopamine or serotonin.
- Large dense core vesicles are packaged at or near the nucleus and are filled after synthesis of the peptide. Can have transporter for small molecule in it.
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