Dynamic regulation of calcium influx by G-proteins, action potential waveform, and neuronal firing frequency

J Neurosci. 1998 Sep 1;18(17):6757-66. doi: 10.1523/JNEUROSCI.18-17-06757.1998.


The time course of Ca2+ channel activation and the amplitude and rate of change of Ca2+ influx are primarily controlled by membrane voltage. G-protein-coupled signaling pathways, however, modulate the efficacy of membrane voltage on channel gating. To study the interactions of membrane potential and G-proteins on Ca2+ influx in a physiological context, we have measured N-type Ca2+ currents evoked by action potential waveforms in voltage-clamped chick dorsal root ganglion neurons. We have quantified the effect of varying action potential waveforms and frequency on the shape of Ca2+ current in the presence and absence of transmitters (GABA or norepinephrine) that inhibit N current. Our results demonstrate that both the profile of Ca2+ entry and the time course and magnitude of its transmitter-induced inhibition are sensitive functions of action potential waveform and frequency. Increases in action potential duration enhance total Ca2+ entry, but they also prolong and blunt Ca2+ signals by slowing influx rate and reducing peak amplitude. Transmitter-mediated inhibition of Ca2+ entry is most robust with short-duration action potentials and decreases exponentially with increasing duration. Increases in action potential frequency promote a voltage-dependent inactivation of Ca2+ influx. In channels exposed to GABA or norepinephrine, however, this inactivation is counteracted by a time- and frequency-dependent relief of modulation. Thus, multiple stimuli are integrated by Ca2+ channels, tuning the profile of influx in a changing physiological environment. Such variations are likely to be significant for the control of Ca2+-dependent cellular responses in all tissues.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / drug effects
  • Calcium Channels / physiology*
  • Cells, Cultured
  • Chick Embryo
  • GTP-Binding Proteins / physiology*
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiology*
  • Ion Channel Gating*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • gamma-Aminobutyric Acid / pharmacology


  • Calcium Channel Blockers
  • Calcium Channels
  • gamma-Aminobutyric Acid
  • GTP-Binding Proteins
  • Calcium