1. Excitable cells and their biochemistry David Taylor dcmt@liv.ac.uk http://www.liv.ac.uk/~dcmt

2.  When you have worked through this you should be able to  Remember the function of the cell membrane and definition of membrane potential  Describe the function of the axon and the definition of action potential  Describe the physiology of chemical transmission at the neuromuscular junction  Describe the physiology of synapses, excitatory and inhibitory, CNS neurotransmitters, the post-synaptic potential, including long-term potentiation as a special type of neuronal response  Receptors, Neurotransmitters, Neuromodulators – only the most important Learning objectives

3.  These slides are available with all my other lectures on my website http://www.liv.ac.uk/~dcmthttp://www.liv.ac.uk/~dcmt  In the text books: Chapters 1,2, and 5 in Preston and Wilson (2013) Chapter 2 and 8 in Naish and Court (2014) Resources

4. First  Remember what the membrane looks like Fig 2.34 in Naish and Court (2014)

5. Resting Membrane Potential Cells in the body are mostly impermeable to Na + and mostly permeable to K + and Cl - Intracellular proteins are negatively charged and can’t leave the cell. When the cell is “at rest” the membrane potential is a compromise between the charge carried by the diffusible ions, and the concentration gradient for each ion Normally this is about -90mV, or -70mV in excitable cells

6. The action potential  e.g. in neurones -70 mV -55mV +40mV Fully permeable to Na +(+40mV) Fully permeable to K + (-90mV) 1mS Resting membrane potential (-70mV)

7.  The depolarisation needs to be big enough to open the voltage activated sodium channels.  If it isn’t nothing happens…. All or nothing….

8. The action potential  e.g. in neurones -70 mV -55mV +40mV VANC open VANC close Fully permeable to Na +(+40mV) Fully permeable to K + (-90mV) 1mS stimulus Resting membrane potential (-70mV)

9. The action potential -70 mV -55mV +40mV VANC open VANC close Fully permeable to Na +(+40mV) Fully permeable to K + (-90mV) 1mS stimulus Resting membrane potential (-70mV) gNa + gK +

10. The wave of depolarisation ---------- ++++++++++ +-+------- --++++++++ -+-+------ ++ - -++++++

11. The synapse Figure 8.28 from Naish & Court (2014)

12. At the synapse In response to depolarisation Voltage-dependent Ca 2+ channels open Which allows vesicles containing neurotransmitters to fuse with the membrane The neurotransmitter crosses the synaptic cleft And binds to receptors…..

13.  Small waves of depolarisation (epsp)  Or hyperpolarisation (ipsp) Post synaptic potentials 1mS 10mV 1mS 10mV

14.  Excitatory post synaptic potentials (epsp) are caused by excitatory transmitters (e.g. glutamate NMDA receptor)  Inhibitory post synaptic potentials (ipsp) are caused by inhibitory transmitters (e.g. glycine receptor)  And GABA (γ-amino butyric acid) opens chloride channels (which makes the membrane less excitable)  Summation can be spatial or temporal  If there is enough depolarisation to open the voltage activate sodium channels – then you get an action potential Summation Summation and transmitters are exceptionally well covered in Chapter 5 sections III and IV of Preston and Wilson (2013)

15.  This is believed to be one of the mechanisms underlying memory  Repeated activity causes the production of more receptors – thereby strengthening the connection within the pathway/network Long-term potentiation p.400-401 Naish & Court (2014)

16.  Postsynaptically  NMDA activation increases intracellular Ca 2+  Persistent activation of CaMKII (Calcium/calmodulin dependent protein kinase) causes AMPA receptor phosphorylation  Phosphorylation of AMPA receptor makes the cell (increasing conductance – i.e. increasing the effect of glutamate)  It also causes the insertion of more AMPA receptors in the membrane (increasing the effect of glutamate) How does LTP happen?

17.  Easiest to learn as you go along!  But as you read about them or revise…, try and work out whether they are  Ionotropic – mediating ion fluxes  Nicotinic ACh increasing Na + influx  Metabotropic – acting through a second messenger pathway  Muscarinic Ach - which works through G-proteins to modulate ion channel activity Receptors, neurotransmitters and neuromodulators Figure 5.3 in Preston and Wilson (2013) Table 5.2 is excellent as an overview of possibilities – but do NOT try to memorise it!