Dynamic regulation of calcium influx by G-proteins, action potential waveform, and neuronal firing frequency.
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.
Departments of Neuroscience and Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
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D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D019204:GTP-Binding Proteins / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015640:Ion Channel Gating; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D005680:gamma-Aminobutyric Acid; D019204:GTP-Binding Proteins; D002118:Calcium