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Understanding Pacemaker Currents in Neurons: Insights from Experimental Neuroscience

Join us for the Summer Course on Experimental Neuroscience at the School of Neuroscience in Torino, Italy. Led by Emilio Carbone, this course will delve into the intricate mechanisms of pacemaker currents in neurons and excitable cells. Attendees will explore the different action potentials and the roles of voltage-gated Na+ and K+ channels, as well as Ca2+-activated K+ channels. The course emphasizes practical insights into how these ion currents shape neuronal activity, providing a comprehensive overview for researchers and students in the field.

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Understanding Pacemaker Currents in Neurons: Insights from Experimental Neuroscience

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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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