1. Lecture 2 Synapses Neuron-cell communication http://biolpc22.york.ac.uk/632/nervelectures.html

2. Aim nto know: u mechanism of synaptic action u drugs which interfere with synaptic action u diseases of synapses

3. Reading Matter nBook u Nicholls DG (1994) Proteins Transmitters and Synapses. Blackwell nPapers: u Jessell TM, Kandel ER (1993) Synaptic trans- mission - a bidirectional and self-modifiable form of cell-cell communication Cell 72S 1-30 u Whittaker, V. (1990) The contribution of drugs and toxins to understanding of cholinergic function Trends Pharm Science 11: 8-13 (in the photocopy collection)

4. Revision nNeurons have channels u voltage gated u ligand gated nResting and action potentials depend on voltage gated channels nConnections between neurons usually called synapses

5. Electrical connections nMembrane resistance too high for direct current flow from cell to cell gap junction

6. Chemical connections nrelease chemical transmitter nrespond with receptors nadvantages u effective u excite or inhibit u variable gain ndisadvantages u slower than electrical [??]

7. Examples of synaptic connections nExamples from snail neurons u Excitation u Inhibition

9. Schematic diagram nneuromuscular junction

10. Freeze fracture nresting nstimulated

11. Quantal release nMiniature EPSP u time traces n Stimulated EPSP u overlaid traces EPSP - excitatory post-synaptic potential

12. Ca ++ needed for release nCa ++ dye in presynaptic neuron n[Ca] rises at end of action potential

13. Ca ++ block stops synapse npresynaptic Vm (voltage clamp) npresynaptic I Ca ++ npostsynaptic Vm

14. Ca ++ block stops synapse npresynaptic EGTA blocks transmission controlEGTA

15. Vesicle fusion cycling nVesicle cycling? u fusion hypothesis u kiss & run nclathrin coating fusion kiss & run

16. Synaptic Toxins ntetanus & botulinum toxins u blocks transmitter release F interacts with (vesicle/membrane proteins) u produced by Clostridium bacteria

17. ACh cycling ACh pumped into vesicle ACh esterase

18. Summary so far ntransmitter is stored in vesicles nvesicles released calcium influx nearby ncalcium influx triggered by depolarisation from action potential

19. Pharmacology of receptors nmany kinds of receptors u ACh u glutamate, glycine u serotonin, dopamine u peptides, FMRFamide nseparate pharmacologically u each receptor binds its own unique profile of drugs

20. Pharmacology of receptors nNicotinic ACh receptor u agonist - nicotine, succinylcholine u antagonist - curare, bungarotoxin nMuscarinic ACh receptor u agonist - muscarine u antagonist - atropine

21. Ionotropic & Metabotropic nIonotropic u receptor binding opens hole u ions flow through nmetabotropic u receptor binding activates G-protein u requires second messenger u 7 transmembrane format u phosphorylates another protein [channel]

22. Second messengers nmake synapses slow ncAMP nIP3/DAG/PKC narachidonic acid = = norepinephrine

23. How does 5-HT act? napply 5-HT to cell npatch elsewhere

24. Effect of 5-HT n5-HT could u block a channel u reduce chance of opening u increase chance of closing u reduce current 5-HT = = serotonin

25. Effect of 5-HT n5-HT closes K + channels u channel size the same u reduced chance of opening

26. Summary so far ntransmitter is stored in vesicles nvesicles released calcium influx nearby ncalcium influx triggered by depolarisation from action potential nmultiple kinds of receptor u ionotropic / metabotropic u different transmitters

27. Excitation and inhibition temporal summation spatial summation

28. Reversal of IPSPs nInhibitory post- synaptic potentials reverse at -70 (K + ) or -50mV (Cl - )

29. Pre- & Post- synaptic inhibition nPost-synaptic inhibition leads to summation of excitatory and inhibitory transmitter nPre-synaptic inhibition occurs between two axons u it prevents release of transmitter

30. Transmitters & disease nmyasthenia gravis u autoimmune response to ACh receptor nParkinson’s disease u loss of dopaminergic neurons

31. Confusing points to watch out for nNote the difference between u inhibition and antagonism u pre- and postsynaptic inhibition u conduction and conductance

32. Summary to end ntransmitter is stored in vesicles nvesicles released calcium influx nearby ncalcium influx triggered by depolarisation from action potential nmultiple kinds of receptor u ionotropic / metabotropic F fast/slow u different transmitters nexcitatory / inhibitory