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Voltage-dependent noradrenergic modulation of omega-conotoxin-sensitive Ca2+ channels in human neuroblastoma IMR32

A Pollo1, M Lovallo, E Sher

  • 1Department of Anatomy and Human Physiology, Torino, Italy.

Pflugers Archiv : European Journal of Physiology
|October 1, 1992
PubMed

Insights

Noradrenaline inhibits high-voltage-activated (HVA) Ca2+ channels in neuroblastoma cells via alpha 2-adrenergic receptors. This G protein-mediated inhibition is voltage-dependent and can be reversed by specific voltage protocols.

Area of Science:

  • Neuroscience
  • Molecular Pharmacology
  • Ion Channel Physiology

Background:

  • High-threshold (HVA) Ca2+ channels are crucial for neuronal function, regulating neurotransmitter release and gene expression.
  • Noradrenaline, a key neurotransmitter, modulates neuronal excitability through various receptor systems.
  • Human neuroblastoma IMR32 cells express a significant population of HVA Ca2+ channels.

Purpose of the Study:

  • To investigate the effects of noradrenaline on HVA Ca2+ channels in IMR32 cells.
  • To elucidate the specific receptor subtypes and signaling pathways involved in noradrenaline's action.
  • To characterize the voltage-dependence and kinetic properties of noradrenaline-induced channel modulation.

Main Methods:

  • Electrophysiological recordings (Ba2+ currents) in IMR32 cells.
  • Application of noradrenaline and related agonists/antagonists.
  • Voltage-clamp protocols including pre-pulses and ramp potentials.
  • Pertussis toxin treatment and intracellular application of GTP analogs.

Main Results:

  • Noradrenaline (10-50 microM) inhibited HVA Ba2+ currents by 50-70% and slowed activation kinetics between -20 mV and +10 mV.
  • Inhibition was dose-dependent (IC50 = 84 nM), mediated by alpha 2-adrenergic receptors, and selective for omega-conotoxin-sensitive channels.
  • Facilitation at more positive voltages or via conditioning pre-pulses recruited ~80% of inhibited channels, with slow re-inhibition (tau r 36-45 ms).
  • G protein involvement was confirmed by GTP[gamma S] and GDP[beta S] experiments, and pertussis toxin sensitivity.
  • Kinetic modeling suggested direct G protein modulation of voltage-dependent gating.

Conclusions:

  • Noradrenaline inhibits HVA Ca2+ channels in IMR32 cells through a pertussis toxin-sensitive G protein-coupled pathway involving alpha 2-adrenergic receptors.
  • The inhibition is voltage-dependent, with channels being more inhibited at rest and recruitable by depolarization.
  • These findings provide insights into the presynaptic regulation of Ca2+ channel function by noradrenergic systems.

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