Excitable cells and their biochemistry David Taylor dcmt@liv.ac.uk http://www.liv.ac.uk/~dcmt Learning objectives 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 Resources These slides are available with all my other lectures on my website http://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) First Remember what the membrane looks like Fig 2.34 in Naish and Court (2014) Resting Membrane Potential • • • • • Cells in the body are mostly impermeable to Na+ and mostly permeable to K+ and ClIntracellular 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 The action potential e.g. in neurones Fully permeable to Na+(+40mV) +40mV Resting membrane potential(-70mV) -55mV -70 mV Fully permeable to K+ (-90mV) 1mS All or nothing…. The depolarisation needs to be big enough to open the voltage activated sodium channels. If it isn’t nothing happens…. The action potential e.g. in neurones +40mV VANC close Fully permeable to Na+(+40mV) VANC open Resting membrane potential(-70mV) stimulus -55mV -70 mV Fully permeable to K+ (-90mV) 1mS The action potential VANC close +40mV Fully permeable to Na+(+40mV) VANC open gNa+ gK+ stimulus Resting membrane potential(-70mV) -55mV -70 mV Fully permeable to K+ (-90mV) 1mS The wave of depolarisation + - + - + + - + + - + - + - + + - + - + - + + - + - + - + - + - + - + - + - + - + - + - + - + - + - + - + - + - The synapse Figure 8.28 from Naish & Court (2014) At the synapse • • • • • In response to depolarisation Voltage-dependent Ca2+ channels open Which allows vesicles containing neurotransmitters to fuse with the membrane The neurotransmitter crosses the synaptic cleft And binds to receptors….. Post synaptic potentials Small waves of depolarisation (epsp) 10mV 1mS Or hyperpolarisation (ipsp) 10mV 1mS Summation 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 and transmitters are exceptionally well covered in Chapter 5 sections III and IV of Preston and Wilson (2013) Long-term potentiation 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 p.400-401 Naish & Court (2014) How does LTP happen? Postsynaptically NMDA activation increases intracellular Ca2+ 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) Receptors, neurotransmitters and neuromodulators 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 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!