Neurotransmission and Modulation Flashcards
What is the Nerst Equation?
RTln([ionint])/zf ln([ionext])
Describe the structure of pentameric ligand gated ion channels (give examples):
- 5 subunits (2α,β, γ, δ)
- Each subunit contains 4 sequences (M1-4)
- M2 region is a pore loop where ligand can attach
Examples: nAChR (excitation); GABAa (inhibition); GlyR (inhibition)
What is the structure of the nAChR channel?
- Pentameric ligand gated ion channel
- 2 ACh bind to pore loops (on M2 sequence)
- Allows the passage of cations (Na+, K+, Ca2+)
- Causes depolarisation and excitation
Name tetrameric ligand gated ion channels and briefly describe their structure.
- Mainly glutamate receptive
Examples: AMPA; Kainate (GluK); NMDA
What is the structure of the Nav channel and why is it significant during depolarisation?
- 4 subunits each with sequences S1-6
- Pore loop between S5-6 which forms channel
- S4 is voltage sensitive
Significance:
- Probability of one domain being open is m
- Probability of voltage inactivated domain being open is h
- Therefore total probability is m^3h
- Probability of opening increases with depolarisation
Assumes all the domains are independent (big assumption)
How was the K+ channel discovered?
- ‘Shaker’ mutant in Drosophila acted same as WT exposed to K channel inhibitor
- Implied channel responsible for K+
Describe current-voltage experiments by Hodgkin/Huxley
Transient inward and delayed outward current seen
Ion substitution experiments:
- Determined Na+ caused inward current and resulted in depolarisation
- Determined K+ caused outward current
Channel blocking experiments
- Tetrodoxin blocks Nav channel
- No action potential then stimulated
What is saltatory conduction and how does it work?
Depolarisation jumps between nodes leading to faster conduction and lower metabolic load.
Mechanism:
- Raises capacitance due to myelination
- Oligodendrocytes in CNS and Schwann cells in PNS
- Creates elongated local currents
What is the purpose of the hyperpolarisation?
- Prevents antidromic (backwards) travel
- Increases re-activation rate of deactivated Nav channels
- Therefore shortens the absolute and relative refractory periods
- Reduces risk of overstimulation (e.g. epilepsy)
How do action potentials code given they are all-or-none?
- Spike frequency coding (larger current = higher frequency)
- Pattern of APs (regular/irregular/intrinsic bursts)
- Width of AP (depending on temperature and kinetics (e.g. KIR slower vs. type A K+ channels)
- Can be modulated by other chemicals
- Repolarisation can be accelerated/decelerated (e.g. by Ca2+ channel activation)
What is passive linear integration? (give examples)
The combination of all incoming signals in a dendrite, changing the probability of progagating an AP>
Examples:
- EPSPs
- IPSPs
- Morphology (how many synapsing dendrites and amount of branching)
- Shunting inhibition
What is shunting inhibition? What is its use?
- Opening Cl- channels
- Since Ecl is close to resting potential this does not change membrane potential significantly
- Decreases change of AP propagating
Use: filters out signal noise since excitatory currents effectively divided by amount of inhibitory input.
Which receptors and molecules result in EPSP and IPSP production?
EPSPs: glutaminergic synapses (distal part of dendrites)
- AMPA receptors are rapid
- NMDA type receptors and slower and can be Mg2+ dependent
- Both have intrinsic Na+/Ca2+ channels causing excitatory currents
- Kainite receptors e.g. GLUK4
IPSPs:
- GABAergic or glycinergic at proximal dendrite sites
- Have integral Cl- channel repolarising the cell
What is active integration and what evidence supports it?
Dendrites propagating/initiating an AP.
Evidence: simultaneous patch-clamp recordings in soma and dendrites
Where can back propagation occur?
- When Nav1.2 channels present (do not inactivate)
- For spike timing dependent plasticity.
Contrast neurotransmitters and neuromodulators:
Time course of action: NT much faster (ms rather than mins/hrs)
Release-effect coupling: NTs strongly coupled to effect; NMs have 2nd messengers which outlast their release
Information route: NT = specific (one cell to next); NMs = non specific populations
What is a ‘brain state’ and how might it be achieved using neuromodulators?
Where activity of nearly all brain altered e.g. asleep or awake state
Using modulators such as DA, NA, SHT, HA which amplify their signals using GPCRs (since only a few cells secrete them).
Describe the structure of an electrical gap junction synapse:
- Tight electrical coupling
- Each cell membrane has hemi-channels of connexins which are aligned
- Tetra membrane spanning proteins dock hemichannels in place
- Synchronises electrical activity so common in interneurons of neocortex
- Transmission occurs in both directions
How was vesicular release discovered?
- Mepps recorded post-synaptically
- Always in quanta of a similar size
- Suggested vesicular release
What roles do glial cells have? (5 points)
- Provide structural support
- Take up neurotransmitter to stop stimulation.
- Spatial buffering of K+
- Metabolic support e.g. astrocyte foot processes which provide lactate for respiration
- Glutamatergic signalling support
- Control of channels using gliotransmitters
Give an example of a gliotransmitter and describe its mechanism of action:
- L-serine converted to D-serine
- By enzyme racemase in glial cells
- D-serine acts as a co-agonist for NMDA receptors
- Increasing long term potentiation
Detail the different categories of neurotransmitter and give an example of each:
Neuropeptide (8-30 aas):
- Orexins and hypocretins for wakefulness
Small molecules (catecholamines):
- DA, SHT, HA, NA, ACh
Amino acids:
- GABA, glycine, glutamate, asparagine
Gaseous:
- CO, NO
- Not vesicularly contained as can freely diffuse
Where is dopamine produced and what is its main function?
- Substantia nigra
- For voluntary movement and reward
- Depletes in Parkinson’s disease
