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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. Why are neurons so interesting ? Fast signalling

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Welcome to 725

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  1. 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

  2. Neurons • Why are neurons so interesting ? • Fast signalling • Specific connections • Long distances • Key features: • Need glia • Ion channels • Synaptic transmission

  3. Glia • About 100 times more glial cells than neurons • Support neurons

  4. Human CNS

  5. Revision – cell shape • Axon • Dendrites • Soma

  6. Channel distribution • Non-uniform • Different in cell body and axon/dendrites • Myelinated axons – Na channels at node of Ranvier K orange; Na red

  7. Na channel is anchored

  8. Node of Ranvier Caspr (axon) + cell adhesion molecule • How does it develop? Cell adhesion molecule recruits ankyrin

  9. Node of Ranvier • How does it develop? Cam x 3 Caspr in axon, linked to cell adhesion molecule in Schwann

  10. Summary so far • Neuronal organisation is complex • Cell geometry • Channel distribution • Signalling by cell-cell interaction important for organistion

  11. 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)

  12. 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

  13. Action potentials in Myelinated Unmyelinated Cell bodies Dendrites Snails Note differences in time scale! Not all APs are equal

  14. Action potentials in Myelinated Unmyelinated Cell bodies Dendrites Snails Mammals are different to amphibians Not all APs are equal

  15. Mammals have many less K channels AP depends on inactivation of Na current to end Not all APs are equal

  16. 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

  17. VC- refractory period • Two pulse experiment • K-current blocked • Na current only

  18. 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)

  19. Is it really gating current? • Two pulse experiment • K-current blocked • Na current only Plot initial Na vs gating current

  20. Mostly ? 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

  21. Summary point • Macroscopic analysis shows: • Voltage sensitivity important in axons • Physiological diversity to reflect anatomical diversity • Implies cellular diversity

  22. Use a small patch of membrane Fixed voltage Measure current Revision – patch clamp

  23. Summation of the effects of individual channels give the macroscopic result Summated channels

  24. Properties of channels • Obey Ohm’s law • Ions flow freely through open channels • Channels selective for particular ions

  25. Channels flow freely Transporters need energy ATP ion gradient Channels vs transporters

  26. 4 repeats of 6 transmembrane regions S4 mutations affect opening S6 line the pore Molecular biology

  27. Most mutations probably fatal before birth Mutations for disease?

  28. Similar genes encode channels with different ionic specificity Channel radiation K cyclic Ca Na

  29. Inactivation (closing) Ball and chain mechanism Opening and closing?

  30. Mutagenesis of +ve charged amino-acids affects voltage sensitivity Activation (opening) • Helix screw model + residues

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

  32. Alternative splicing

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

  34. How often in ion channels? • 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

  35. Conclusion • 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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