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Molecular + Cellular Neuro > Excitability and Ion channels II > Flashcards

Excitability and Ion channels II Flashcards

1
Q

Explain the activity occurring at the synapse - steps (9)

A

1) AP
2) Ca2+ influx (activated by CaV2 channels)
3) exocytosis - vesicles release neurotransmitters to act on
4) ligand gated ion channels or G protein couple receptors
5) neurotransmitter r on presynaptic cell = build up of neurotrans = excitation of post synap cell
6) act on either transport protein (back into pre-synap) or neurotransmitter degradation or uptake by glial cells
7) calphrin mediated endocytosis
8) large dense core granules
9) release from distant site - repeated simulation

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2
Q

How do we measure the activity? (2)

A

electrophysiology - by measuring capacitance (ability of the membrane to store charge) - specifically the changes in capacitance

  • the flow of ions following activation
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3
Q

what does a large, wide spike suggest? (1)

A

multiple vesicles binding to the membrane + being released

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4
Q

what pattern is observed from large vesicles? (2)

A

ca2+ influx is always the triggering step
= neurotransmitter release is steeply dependent on the calcium concentration in pre-synap terminal

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5
Q

experiment w/ bath loaded w/ caged ca2+ + UV light (4)

A
  • bound ca2+ released in response to to flashes of UV light
  • controlling light = control ca2+ release
    -non-linear relationship b/w ca2+ and it’s release
  • release of transmitters requires the binding of 5 ca2+ ions to a ca2+ sensing synaptic vesicle protein
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6
Q

measuring responses in the post-synaptic cell as a means of measuring neurotransmitter release experiment - 3 panels (6)

A

a) depolarising pulse
b) depolarising pulse + calcium (before stimulus)
c) calcium (after stimulus)

  • only response was recorded was in B = sufficient mechanical mechanisms to release neurotransmitters
  • no biolog response if ca2+ added after depolarisation

= must conclude ca2+ move from the extracellular space into intracellular to elicit a response

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7
Q

explain the SNARE Complex (both complexes)(3 +4)

A

exocytosis mediated by SNARE Complex

1)= tight interaction b/w synaptobrevin + synapsin + SNAP 25

2)Munc18 interacts w/SNARE Complex (essential for physical fusion)

1)2nd protein complex forms when Rab3A (vesical protein) binds to Munc13 + RIM

2) SNARE + Rab3A complexes = functionally linked because of an interaction b/w Synaxton + Munc13

3)Munc13 complex likely to inhibit the formation of the SNARE Complex = vesicle protein synaptotagmin serves as a ca2+ sensor for exocytosis + may also interact w/ RIM

4)synaptic vesicles also contain membrane transporters for reuptake -> synapsin is important for agnating the availability of vesicles in the reserve pole

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8
Q

Explain synapsin’s background + interaction (3)

A

-substrate for protein kinase A + Ca2+ calmoldulin binding protein kinase 1 = nerve terminal depolarised
= ca2+ enters synapsin = becomes phosphorylated by kinase + released from vesicle
=(mobilises reserve pool of vesicle transmitter for release)

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9
Q

name the 2 genetic deletion/application of synapsin antibodies (2)

A

-decrease in the no. of synaptic vesicles in the nerve terminal
-decrease in the ability to maintain a high rate of neurotransmitters release during repetitive stimulation

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10
Q

what do SNARE proteins do? (2)

A

catalyse the fusion of the vesicles w/plasma membrane because membrane bilayer is stable

(as it needs to overcome a large unfavourable Ea -> accompanied by family of fusion proteins (SNARES))

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11
Q

SNARE Complex summarised (4)

A

1) Synaptobrevin interacts w/2 plasma membrane target proteins
- synactin
-SNAP 25
= forms tight complex, brining the vesicle + pre-synaptic membranes in close opposition

2) Munc18 binds to SNARE complex

3) Ca2+ influx = triggers rapid fusion of vesicle + plasma membranes = snare complex now in plasma membrane

4)NSF + SNAP(new) proteins bind to complex = cause it to show association in ATP dependent reaction

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12
Q

CaV2 subfamily (2)

A

-all responsible for neurotransmitter release + dendritic ca2+ transients

CaV 2.1, 2.2, 2.3

Current types: N, P/Q, R

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13
Q

CaV2 subfamily in neurotransmitter release (3)

A
  • Anchored in the active zone – nanodomain (CaV2.1 + 2.2)
  • Regulated by voltage AND external agonists (e.g. dihydroprodrene = incr. channel openings) and antagonists (e.g. boscovity = inhibit neurotrans release)
  • Also regulated by some GPCRs - specifically GPCR’s coupled to GQ pathway = reduces PIP2 in CaV2
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14
Q

GPCRs + CaV2 subfamily explained

A
  • they inhib CaV2 channel via G-beta, gamma subunits
  • coupled to GQ pathway = inhib by decreased PIP2 levels by modulation involving c terminal domain of CaV2 channel (incl. CDK5 phosphoryl mediated phosphorylation of a conserved serine of the CaV2.2

= increased channel opening probability = Ca2+ dependent inactivation (CDI) only present in Cav2.2 + 1) + Ca2+ dependence

= mediated by calmodulin binding to sites of proximal c terminal domain

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15
Q

Body signals in normal physiology- steps (3)

A

1) signal travels through body
2) gets to cell = activates receptor
3) physiological response (changes in morphology/shape of cell)

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16
Q

How does the cell translate an external signal into an internal signal? - 4 ways (4)

A

Direct: coupled directly to the drug
-Coupling to ion channels (ionotropic receptors)

Indirect:
- G protein coupled receptors (GPCRs) (metabotropic receptors/ 7 transmembrane r’s) -> coupled to a protein (50% of drug targets + responsible for most sensory signals in our body)

-Enzyme linked receptors -> coupling to enzyme

-Nuclear receptors (DNA transcription) -> bind to DNA = changes in DNA transcription

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17
Q

Name the key fast transmitters in the CNS (3)

A

Excitatory:
-Glutamate –> iGluRs (AMPA, Kainate, NMDAr) or mGluRs (Grp i/ii/iii)

Inhibitory:
-y-amino butyric acid (gaba) –> iGABARs or GABAbRs
-glycine –>iGlyRs

18
Q

What are some other fast + slow transmitters (7)

A

Other fast synaptic transmitters:
ACh (nAChRs), 5HT (5HT3R), ATP (P2XRS)

Also many slow transmitters which often work by “volume transmission”-
DA, NA, 5HT, ACh, Neuropeptides, Histamine etc

19
Q

Glutamate quick summary (2)

A

-Glutamate really is the major transmitter for synaptic communication

-Accounts for >90% of synaptic connections in the human brain

Many papers start “Glutamate is the major excitatory neurotransmitter in the vertebrate
nervous system….

20
Q

AMPA Receptor Subunit Topology - learn diagram

A

Image
- Tetramer: for AMPA receptors GluA1-4 subunits in any combination

  • 3 TM domains - M1, M3, M4 — redundant loop in M2

-*Q/R site – determines Ca2+ permeability of receptor

21
Q

Properties of AMPA Receptors (5)

A
  • Mediate majority of fast excitatory synaptic transmission (mainly postsynaptic localization) – AMPARs non-selective cation channels permeable to Na+ (goes in) and K+ (goes out) and in some cases Ca2+
  • Like all ionotropic glutamate receptors comprised of four subunits = tetrameric receptor
  • 4 different AMPA receptor subunits in mammals GluA1, GluA2, GluA3 and GluA4 these “mix and match” = produce subtly different receptors
  • AMPA receptors containing GluA2 subunit have very low Ca2+ permeability
  • due to mRNA editing – positively charged arginine (R) residue expressed instead of neutral glutamine (Q) in pore forming M2 region of GluA2
  • = activation of all AMPA receptors = influx of Na+ but these receptors are only permeable to
    Ca2+ only in the absence of any GluA2(R) subunits (and most AMPA receptors have GluA2(R))
22
Q

Kainate Receptor Subunit Topology - (4)

A
  • 3 TM domain + Redundant loop

-For kainate receptors GluK1-5 subunits – GluK4 or GluK5 expressed alone in a tetramer do not form functional receptors

*Q/R site – determines Ca2+permeability of GluK1 and K2

-GluK1 and GluK2 undergo RNA editing at a pore Q/R site and this is regulated in development

Impermeable to ca bless in early stages of dev (like AMPA)

23
Q

NMDA Subunits - NR1 + NR2 (3)

A

-NMDA receptors are heterotetramers of two GluN1 (NR1) subunits and two GluN2 (NR2) subunits

-GluN1 (NR1) comes form a single gene but has 8 different splice forms…
– 4 different GluN2 genes which are differentially expressed in different brain areas and at different
ages

NR1 contains glycine binding site, NR2 contains glutamate binding site

24
Q

3 important NMDA properties made up of subunits (3)

A

Three important properties:
* High Ca2+ permeability
* Mg2+ ions block channel at negative (i.e. resting) membrane potentials
* Glycine is a necessary co-agonist (in addition to glutamate)

NR1 contains glycine binding site, NR2 contains glutamate binding site

25
Q

Mg2+ block of NMDA receptors is voltage-dependent (2)

A

for Mg2+ block of NMDAR :
- channel must be open i.e. glycine and glutamate must be bound to their binding sites on the NMDA receptor

Thus Ca2+ entry through NMDARs is dependent on pre- and postsynaptic elements being active at the same time i.e. the NMDAR is a coincidence detector.

26
Q

How is the Mg2+ block of NMDAr channel removed (4)

A

As membrane potential is depolarized = the Mg2+ block of the NMDA receptor channel is removed

-AMPARs often present at same synapse as NMDARs

-Activation of AMPARs depolarises the
membrane sufficiently to remove Mg2+ block of NMDARs

-By voltage of ~ -35 mV the Mg2+ block of the
NMDA receptor channel is mostly removed i.e.
inward current through the NMDAR is voltage
dependent as well as transmitter gated

27
Q

NMDAr synaptic physiology pattern vs AMPA (1)

A

Mediates a SLOWLY rising LONG LASTING excitatory
synaptic response via Na+ and Ca2+ entry through channel compared to AMPA.

28
Q

NMDAr + Synaptic Plasticity (2)

A

The ability to change strength of synaptic
connections and consolidate new pathways in the CNS). NMDARs are involved in two processes - LTD + LTP

Via NMDAr Ca2+ influx

29
Q

What does a current clamp measure? (1)

A

measures the membrane potential

30
Q

What does a voltage clamp measure? (1)

A

records the current after being fixed at a specific membrane potential

31
Q

What is Ohm’s law? (3)

A

V = I x R

  • Voltage (V) due to separation of charge
    Volts

-Current (I) represents the flow of charge
Ampere or Amps

-Resistance (R) oppose current flow Ohms

32
Q

Current clamp (3)

A

Electrophysiological amplifiers are capable of stimulating the cell by injecting current.

Negative Current = causes hyperpolarisation of the membrane

Therefore, intracellular recordings of voltage are called ‘current clamp’

33
Q

Voltage Clamp (1)

A

In voltage clamp, we are measuring what the amplifier is doing to keep the cell at Vclamp.

34
Q

current vs voltage clamp in experiment - analogy of bank balance (3)

A

In current clamp VM will become more positive as it moves towards ENa

In voltage clamp VM cannot change (clamped). To
counteract the flow of +ve Na+ions into the cell, the
amplifier injects negative current

Analogy: In voltage clamp we are monitoring the ‘deposits’ and ‘withdrawals’ which are in the opposite direction to the ‘activity’

35
Q

EPSP vs EPSC (2)

A

Why is the EPSC negative current?

The amplifier must inject negative current to maintain the cell at -80 mV to oppose the flow of
positively charged ions via the glutamate receptor

36
Q

Extracellular recording (3)

A

Place electrode outside and add current to axon = depolarised all CELLS and not one cell = measure activity of one cell (easier)

As positive ions move into the cell, the extracellular
space becomes more negative

We call this a field potential or a fEPSP

37
Q

electrophys recording summary (4)

A
  • Intracellular electrophysiology used to study electrical activity in single cells

-Extracellular electrophysiology used to study electrical activity from groups of cells in one anatomical location

-Current clamp recording can be used to monitor the effects of manipulations (eg drugs) on
membrane potentials

-Voltage clamp can be used to study the underlying biophysical properties of channels in the
membrane and the effects of manipulations (eg drugs) on these

38
Q

What is always the triggering step? (1)

A

The calcium influx

39
Q

4 methods of eliciting a response in detail (4)

A

Ligand gated ion channels: (ms)
Binding of r = confirmation change = influx of Ions -> hyperpolarisation/depolarisation -> cellular effects

GPCRs: (s)
Bind to protein -> either phosphorylation of other proteins or kinases coupled with ion channels

Kinase/enzyme linked r: (hrs)
Receptor linked to it -> protein phosphorylation -> gene transcription -> protein syn

Nuclear r: (hrs)
Hypophilic: elicit response at targets
- mediate gene synthesis = response

40
Q

Glutamergic synaptic transmission + AMPA blockage (2)

A

Mechanism of action: ionotropic

ESPC can be almost completely blocked by selective AMPA r antag eg Telampanel

Molecular + Cellular Neuro (21 decks)

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