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Pacemaker currents in neurons and excitable cells Emilio Carbone

Summer Course on Experimental Neuroscience School of Neuroscience Department of Neuroscience Corso Raffaello 30, 10125 Torino Torino, July 1 2009. Pacemaker currents in neurons and excitable cells Emilio Carbone. Different neuronal APs. Different neuronal APs.

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Pacemaker currents in neurons and excitable cells Emilio Carbone

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  1. Summer Course on Experimental Neuroscience School of Neuroscience Department of Neuroscience Corso Raffaello 30, 10125 Torino Torino, July 1 2009 Pacemaker currents in neurons and excitable cells Emilio Carbone

  2. Different neuronal APs Different neuronal APs from Bean, Nature Review Neurosci. (2007)

  3. Voltage-gated Na+ and K+ channels account for the fast APs fast activating fast inactivating slowly activating non inactivating INa = gNa (Vm – ENa) ENa= +63 mV IK = gK (Vm – EK) EK = -102 mV

  4. Block of V-gated Na+ and K+ channels alter the shape of APs

  5. Ca2+-activated K+ channels do also shape the APs

  6. Ca2+-activated K+ channels do also shape the APs • The big K+ channel (BKCa) • Activation is Ca2+- and V-dependent • Micromolar affinity for Ca2+ • Forms nanodomains with Ca2+ channels • Responsible for fast repolarizations • Is blocked by charybdotoxin, iberiotoxin, paxilline and 0.5 -1 mM TEA+ Marcantoni et al., Cell Calcium 2007

  7. Ca2+-activated K+ channels do also shape the APs • The small K+ channel (SKCa) • Activation is only Ca2+-dependent (regulated by CaM) • Submicromolar affinity for Ca2+ • Forms microdomains with Ca2+ channels • Requires more than one voltage-gated Ca2+ channel to activate • Sensitive to the cytoplasmatic Ca2+ • Responsible of slow repolarization • Is blocked by apamin, insensitive to TEA+ and Cs+

  8. Voltage and Ca2+-gated ion channels contribute to shape the APs SKCa

  9. sympathetic nerve stimulation action potential Ca2+ Ca2+ vesicle circulating adrenaline

  10. Chromaffin cells undergo spontaneous activity at rest

  11. Preliminary observations to identify a pacemaker channel Marcantoni et al., Cell Calcium 2007

  12. Pacemaker channels require peculiar gating properties The L-type channels: Cav1.2, Cav1.3 Cesetti et al., J. Neurosci 2003 Marcantoni et al., submitted 2009 Marcantoni et al., Cell Calcium 2007

  13. Ion currents viewed through the “action potential-clamp” • The voltage comand is not a step but the action potential itself previously recorded from the same cell • This technique allows to record the ion currents during the time course of the AP • It is the most direct way to analyze the kinetics of ion channels while the excitable cell is under functional conditions • It can be applied to any type of excitable cell that fires (neuron, cardiac myocytes, neuroendocrine cells, …)

  14. Na+, Ca2+ and K+ currents during the action potential-clamp INa = gNa (Vm – ENa) IK = gK (Vm – EK) ICa = gCa (Vm – ECa)

  15. Inward Na+ and Ca2+ currents in central neurons from Bean, Nature Review Neurosci. (2007)

  16. Ca2+ currents before and during the AP in chromaffin cells • L-type channels dominate the pre-spike phase with respect to the other high-threshold Ca2+ channels • The experiment suggests that L-type Ca2+ channels are potentially suitable for carrying pacemaker currents during a train of APs

  17. L-type channels carry a pacemaker current in chromaffin cells

  18. In Cav1.3-/- mice a high percentage of chromaffin cells are silent

  19. Strict coupling between L and BKCa channels in central neurons from Bean, Nature Review Neurosci. (2007)

  20. The agonist BayK 8644 enhances the pacemaker L-type currents from Albillos et al. EJN. (1996) from Marcantoni et al. submitted (2009)

  21. Na+ and Ca2+ pacemaker currents in midbrain dopaminergic neurons from Puopolo et al J Neurosci (2007)

  22. Pacemaker currents in dopaminergic neurons from Puopolo et al J Neurosci (2007)

  23. L-type channels control the pacemaker current of dopaminergic neurons

  24. Pacemaker currents in suprachiasmatic nucleus (SCN) neurons from Jackson et al J Neurosci (2004)

  25. Background pacemaker currents in SCN neurons

  26. Suggested readings: Bean B. (2007) Nature Reviews Neuroscience 8:451 Fakler B & Adelman JP (2008) Neuron 59:873 Marcantoni et al (2009) Pflügers Archiv Europ J Physiol 457:1093 Marcantoni et al (2007) Cell Calcium 42:397 Jackson et al (2004) J. Neuroscience 24:7985 Puopolo et al (2007) J. Neuroscience 27:645

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