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Welcome to 725. Cellular and Molecular Neuroscience Chris Elliott & Sean Sweeney Aim: describe the cellular workings of the CNS in health and disease Neurons Glia Blood vessels See http://biolpc22.york.ac.uk/725. Neurons. Why are neurons so interesting ? Fast signalling

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Welcome to 725
Welcome to 725

  • Cellular and Molecular Neuroscience

  • Chris Elliott & Sean Sweeney

  • Aim: describe the cellular workings of the CNS

    • in health and disease

      • Neurons

      • Glia

      • Blood vessels

  • See http://biolpc22.york.ac.uk/725


Neurons
Neurons

  • Why are neurons so interesting ?

    • Fast signalling

    • Specific connections

    • Long distances

  • Key features:

    • Need glia

    • Ion channels

    • Synaptic transmission


Glia

  • About 100 times more glial cells than neurons

  • Support neurons



Revision cell shape
Revision – cell shape

  • Axon

  • Dendrites

  • Soma


Channel distribution
Channel distribution

  • Non-uniform

    • Different in cell body and axon/dendrites

    • Myelinated axons – Na channels at node of Ranvier

K orange; Na red



Node of ranvier
Node of Ranvier

Caspr (axon) + cell adhesion molecule

  • How does it develop?

Cell adhesion molecule recruits ankyrin


Node of ranvier1
Node of Ranvier

  • How does it develop?

Cam x 3

Caspr in axon,

linked to cell adhesion molecule in Schwann


Summary so far
Summary so far

  • Neuronal organisation is complex

    • Cell geometry

    • Channel distribution

  • Signalling by cell-cell interaction important for organistion


Revision electrics
Revision - electrics

  • Current is rate at which ions flow

    • Measure in ions/sec or Amps

  • Voltage is driving force

  • Resistance = V/I

  • Conductance = I/V

    • More current flowing means a bigger hole to flow through

    • Measure in Siemens S (pS)


Revision voltage clamp

Aim: to separate capacitance current (IC) from ionic current

IC only flows when the voltage is changing

Use ion substitution or pharmacological blockers to identify ionic currents

Revision – voltage clamp


Not all aps are equal

Action potentials in

Myelinated

Unmyelinated

Cell bodies

Dendrites

Snails

Note differences in time scale!

Not all APs are equal


Not all aps are equal1

Action potentials in

Myelinated

Unmyelinated

Cell bodies

Dendrites

Snails

Mammals are different to amphibians

Not all APs are equal


Not all aps are equal2

Mammals have many less K channels

AP depends on inactivation of Na current to end

Not all APs are equal


Many types of channels

Ion channels for Na, K, Ca, Cl, etc

Subtypes for each ion may have different characteristics

Here 3 K channels

Maintained

Transient

Off transient

Many types of channels


Vc refractory period
VC- refractory period

  • Two pulse experiment

    • K-current blocked

    • Na current only


Vc gating current

If Na channels are opened by voltage, then they need a voltage sensor

Measure the current when Na and K are blocked

VC- gating current

K current blocked

Na and K current blocked

Na current (subtraction)


Is it really gating current
Is it really gating current? voltage sensor

  • Two pulse experiment

    • K-current blocked

    • Na current only

Plot initial Na vs gating current


Is it really gating current1

Mostly ? voltage sensor

Corresponds to movement of about 3 ionic charges

Also measure using asymmetry of positive and negative pulses, so may be called asymmetry current

Is it really gating current?

“Gating current”

Na current


Summary point
Summary point voltage sensor

  • Macroscopic analysis shows:

    • Voltage sensitivity important in axons

    • Physiological diversity to reflect anatomical diversity

    • Implies cellular diversity


Revision patch clamp

Use a small patch of membrane voltage sensor

Fixed voltage

Measure current

Revision – patch clamp


Summated channels

Summation of the effects of individual channels give the macroscopic result

Summated channels


Properties of channels
Properties of channels macroscopic result

  • Obey Ohm’s law

  • Ions flow freely through open channels

  • Channels selective for particular ions


Channels vs transporters

Channels flow freely macroscopic result

Transporters need energy

ATP

ion gradient

Channels vs transporters


Molecular biology

4 repeats of 6 transmembrane regions macroscopic result

S4 mutations affect opening

S6 line the pore

Molecular biology


Mutations for disease

Most mutations probably fatal before birth macroscopic result

Mutations for disease?


Channel radiation

Similar genes encode channels with different ionic specificity

Channel radiation

K

cyclic

Ca

Na


Opening and closing

Inactivation (closing) specificity

Ball and chain mechanism

Opening and closing?


Activation opening

Mutagenesis of +ve charged amino-acids affects voltage sensitivity

Activation (opening)

  • Helix screw model

+ residues


New hypothesis

Rotation of charged residues in S4 may affect S5 and S6 to change diameter of the pore

New hypothesis


Alternative splicing
Alternative splicing change diameter of the pore


Rna editing
RNA Editing change diameter of the pore

  • ADARs (adenosine deaminases that act on RNA) A → I (treated as G)


How often in ion channels
How often in ion channels? change diameter of the pore

  • Multiple genes in mammals (9)

  • Much alternative splicing

  • Many RNAi editing sites

    • Glu ion channels

    • Serotonin receptor

    • Potassium voltage gated channels

  • In flies,

    • one Na channel gene

    • > 3 alternative spices

    • 10 RNAi editing sites


Conclusion
Conclusion change diameter of the pore

  • Microscopic physiology and molecular studies contribute together to our understanding of channels

  • Mechanism of opening and of closing relates to channel morphology and sequence

  • Evolutionary diversity and adaptation to different functions

  • References


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